1.A.2 The Inward Rectifier K+ Channel (IRK-C) Family

IRK or GIRK channels possess the ''minimal channel-forming structure'' with only a P domain, characteristic of the channel proteins of the VIC family (TC #1.A.1), and two flanking transmembrane spanners. They may exist in the membrane as homo- or heterooligomers. They have a greater tendency to let K flow into the cell than out. Voltage-dependence may be regulated by external K+ , by internal Mg2+ , by internal ATP and/or by G-proteins. The P domains of IRK channels exhibit limited sequence similarity to those of the VIC family. Inward rectifiers play a role in setting cellular membrane potentials, and closing of these channels upon depolarization permits the occurrence of long duration action potentials with a plateau phase. Inward rectifiers lack the intrinsic voltage sensing helices found in many VIC family channels. In a few cases, those of Kir1.1a, Kir6.1 and Kir6.2, for example, direct interaction with a member of the ABC superfamily has been proposed to confer unique functional and regulatory properties to the heteromeric complex, including sensitivity to ATP. These ATP-sensitive channels are found in many body tissues. They render channel activity responsive to the cytoplasmic ATP/ADP ratio (increased ATP/ADP closes the channel). The human SUR1 and SUR2 sulfonylurea receptors (spQ09428 and Q15527, respectively) are the ABC proteins that regulate both the Kir6.1 and Kir6.2 channels in response to ATP, and CFTR (TC #3.A.1.208.4) may regulate Kir1.1a.

Mutations in SUR1 are the cause of familial persistent hyperinsulinemic hypoglycemia in infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion in the pancreas. SUR1 has two nucleotide binding domains, NBD1 (binds ATP) and NBD2 (binds Mg-ADP). Both NBDs mediate nucleotide regulation of pore activity. Kir6.2, unlike many other Kir channels, cannot form plasma membrane functional channels when expressed without SUR1. This is due to a trafficking signal in SUR1 (Partridge et al., 2001). Epsilon toxin from Clostridium perfringens causes inhibition of potassium inward rectifier (Kir) channels, possibly by an indirect mechanism, in oligodendrocytes (Bossu et al. 2020).

The crystal structure (Kuo et al., 2003) and function (Enkvetchakul et al., 2004) of bacterial members of the IRK-C family have been determined. KirBac1.1, from Burkholderia pseudomallei, is 333 aas long with two N-terminal TMSs flanking a P-loop (residues 1-150), and the C-terminal half of the protein is hydrophilic. It transports monovalent cations with the selectivity: K ~ Rb ~ Cs >> Li ~ Na ~ NMGM (protonated N-methyl-D-glucamine). Activity is inhibited by Ba2* , Ca2+ and low pH (Enkvetchakul et al., 2004). 

Kir3 channels control heart rate and neuronal excitability through GTP-binding (G) proteins and phosphoinositide signaling pathways (Doupnik 2008). These channels were the first characterized effectors of the betagamma subunits of G proteins. The crystal structure of a chimera between the cytosolic domain of a mammalian Kir3.1 and the transmembrane region of a prokaryotic KirBac1.3 (Kir3.1 chimera) provided structural insight. This channel has been functionally reconstituted in planar lipid bilayers (Leal-Pinto et al. 2010). The chimera behaved like a Kir channel, displaying a requirement for PIP(2) and Mg2+-dependent inward rectification. The channel was blocked by external tertiapin Q. The three-dimensional reconstruction of the chimera by single particle electron microscopy revealed a structure consistent with the crystal structure. Channel activity could be stimulated by ethanol and activated G proteins but the presence of both activated G-alpha and G-betagamma subunits was required for gating.

GIRK (Kir3) channels are members of the large family of inwardly rectifying potassium channels (Kir1-Kir7). GIRK channels, like all other Kir channels, possess an extrinsic mechanism of inward rectification involving intracellular Mg2+ and polyamines that occlude the conduction pathway at membrane potentials positive to EK. More than 20 high-resolution atomic structures containing GIRK channel cytoplasmic domains and transmembrane domains have been solved. These structures have provided valuable insight into the structural determinants of many of the properties common to all inward rectifiers, such as permeation and rectification, as well as revealing the structural bases for GIRK channel gating (Glaaser and Slesinger 2015).

GIRK channels are abundantly expressed in the heart and require that phosphatidylinositol bisphosphate (PIP2) is present so that intracellular channel-gating regulators such as Gbetagamma (Gβγ)and Na+ ions maintain the channel-open state. Li et al. 2019 determined how each regulator uses the channel domain movements to control gate transitions. Na+ controls the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gbetagamma stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects altered the way by which the channel interacts with PIP2 and thereby stabilized the open states of the respective gates (Li et al. 2019).

The generalized transport reaction catalyzed by IRK-C family proteins is:

K+ (out) K+ (in)

This family belongs to the VIC Superfamily.



Aguilar-Bryan, L., J.P. Clement IV, G. Gonzalez, K. Kunjilwar, A. Babenko, and J. Bryan. (1998). Toward understanding the assembly and structure of KATP channels. Physiol. Rev. 78: 227-245.

Alvin, Z.V., R.M. Millis, W. Hajj-Mousssa, and G.E. Haddad. (2011). ATP-Sensitive Potassium Channel Currents in Eccentrically Hypertrophied Cardiac Myocytes of Volume-Overloaded Rats. Int J. Cell Biol. 2011: 838951.

Amani, R., C.G. Borcik, N.H. Khan, D.B. Versteeg, M. Yekefallah, H.Q. Do, H.R. Coats, and B.J. Wylie. (2020). Conformational changes upon gating of KirBac1.1 into an open-activated state revealed by solid-state NMR and functional assays. Proc. Natl. Acad. Sci. USA 117: 2938-2947.

Aréchiga-Figueroa, I.A., L.G. Marmolejo-Murillo, M. Cui, M. Delgado-Ramírez, M.A.G. van der Heyden, J.A. Sánchez-Chapula, and A.A. Rodríguez-Menchaca. (2017). High-potency block of Kir4.1 channels by pentamidine: Molecular basis. Eur J Pharmacol 815: 56-63.

Ashen, M.D., B. O’Rourke, K.A. Kluge, D.C. Johns, and G.F. Tomaselli. (1995). Inward rectifier K+ channel from human heart and brain: cloning and stable expression in a human cell line. Am. J. Physiol. 268: H506-H511.

Babenko, A.P., G. Gonzalez, and J. Bryan. (1999). Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of KATP channel isoforms. J. Biol. Chem. 274: 11587-11592.

Barbera, N., S.T. Granados, C.G. Vanoye, T.V. Abramova, D. Kulbak, S.J. Ahn, A.L. George, Jr, B.S. Akpa, and I. Levitan. (2022). Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces. iScience 25: 104329.

Bendahhou, S., M.R. Donaldson, N.M. Plaster, M. Tristani-Firouzi, Y.-H. Fu, and L.J. Ptácek. (2003). Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil Syndrome. J. Biol. Chem. 278: 51779-51785.

Bensassi F., Gallerne C., Sharaf El Dein O., Hajlaoui MR., Bacha H. and Lemaire C. (2012). Cell death induced by the Alternaria mycotoxin Alternariol. Toxicol In Vitro. 26(6):915-23.

Beverley, K.M., P.K. Shahi, M. Kabra, Q. Zhao, J. Heyrman, J. Steffen, and B.R. Pattnaik. (2022). Kir7.1 disease mutant T153I within the inner pore affects K+ conduction. Am. J. Physiol. Cell Physiol. [Epub: Ahead of Print]

Black, K.A., S. He, R. Jin, D.M. Miller, J.R. Bolla, O.B. Clarke, P. Johnson, M. Windley, C.J. Burns, A.P. Hill, D. Laver, C.V. Robinson, B.J. Smith, and J.M. Gulbis. (2020). A constricted opening in Kir channels does not impede potassium conduction. Nat Commun 11: 3024.

Boim, M.A., K. Ho, M.E. Shuck, M.J. Bienkowski, J.H. Block, J.L. Slightom, Y. Yang, B.M. Brenner, and S.C. Hebert. (1995). ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms. Am. J. Physiol. 268: F1132-1140.

Bonfanti DH., Alcazar LP., Arakaki PA., Martins LT., Agustini BC., de Moraes Rego FG. and Frigeri HR. (2015). ATP-dependent potassium channels and type 2 diabetes mellitus. Clin Biochem. 48(7-8):476-82.

Borcik, C.G., D.B. Versteeg, R. Amani, M. Yekefallah, N.H. Khan, and B.J. Wylie. (2020). The Lipid Activation Mechanism of a Transmembrane Potassium Channel. J. Am. Chem. Soc. [Epub: Ahead of Print]

Bossu, J.L., L. Wioland, F. Doussau, P. Isope, M.R. Popoff, and B. Poulain. (2020). Epsilon Toxin from Causes Inhibition of Potassium inward Rectifier (Kir) Channels in Oligodendrocytes. Toxins (Basel) 12:.

Bukiya, A.N., S. Durdagi, S. Noskov, and A. Rosenhouse-Dantsker. (2017). Cholesterol Up-regulates Neuron.al G Protein-Gated Inwardly Rectifying Potassium (GIRK) Channel Activity in the Hippocampus. J. Biol. Chem. [Epub: Ahead of Print]

Bushman, J.D., Q. Zhou, and S.L. Shyng. (2013). A Kir6.2 Pore Mutation Causes Inactivation of ATP-Sensitive Potassium Channels by Disrupting PIP2-Dependent Gating. PLoS One 8: e63733.

Caballero, R., P. Dolz-Gaitón, R. Gómez, I. Amorós, A. Barana, M. González de la Fuente, L. Osuna, J. Duarte, A. López-Izquierdo, I. Moraleda, E. Gálvez, J.A. Sánchez-Chapula, J. Tamargo, and E. Delpón. (2010). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proc. Natl. Acad. Sci. USA 107: 15631-15636.

Chen, I.S., M. Tateyama, Y. Fukata, M. Uesugi, and Y. Kubo. (2017). Ivermectin activates GIRK channels in a PIP -dependent, G -independent manner and an amino acid residue at the slide helix governs the activation. J. Physiol. 595: 5895-5912.

Cheng, W.W., D. Enkvetchakul, and C.G. Nichols. (2009). KirBac1.1: it's an inward rectifying potassium channel. J Gen Physiol 133: 295-305.

Choi, S.B., J.U. Kim, H. Joo, and C.K. Min. (2010). Identification and characterization of a novel bacterial ATP-sensitive K+ channel. J Microbiol 48: 325-330.

Clement, J.P., IV, K. Kunjilwar, G. Gonzalez, M. Schwanstecher, U. Panten, L. Aguilar-Bryan, and J. Bryan. (1997). Association and stoichiometry of KATP channel subunits. Neuron 18: 827-838.

Coulson, E.J., L.M. May, S.L. Osborne, K. Reid, C.K. Underwood, F.A. Meunier, P.F. Bartlett, and P. Sah. (2008). p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. J. Neurosci. 28: 315-324.

Country, M.W. and M.G. Jonz. (2021). Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus). J Exp Biol 224:.

Cui, M., K. Xu, K.D. Gada, B. Shalomov, M. Ban, G.C. Eptaminitaki, T. Kawano, L.D. Plant, N. Dascal, and D.E. Logothetis. (2022). A novel small-molecule selective activator of homomeric GIRK4 channels. J. Biol. Chem. 298: 102009.

Dahlmann, A., M. Li, Z. Gao, D. McGarrigle, H. Sackin, and L.G. Palmer. (2004). Regulation of Kir channels by intracellular pH and extracellular K+: mechanisms of coupling. J Gen Physiol 123: 441-454.

Doupnik, C.A. (2008). GPCR-Kir channel signaling complexes: defining rules of engagement. J Recept Signal Transduct Res 28: 83-91.

Du, Y., T. Wang, J. Guo, W. Li, T. Yang, M. Szendrey, and S. Zhang. (2021). Kv1.5 channels are regulated by PKC-mediated endocytic degradation. J. Biol. Chem. 100514. [Epub: Ahead of Print]

Enkvetchakul, D., J. Bhattacharyya, I. Jeliazkova, D.K. Groesbeck, C.A. Cukras, and C.G. Nichols. (2004). Functional characterization of a prokaryotic Kir channel. J. Biol. Chem. 279: 47076-47080.

Epshtein, Y., A.P. Chopra, A. Rosenhouse-Dantsker, G.B. Kowalsky, D.E. Logothetis, and I. Levitan. (2009). Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol. Proc. Natl. Acad. Sci. USA 106: 8055-8060.

Fagnen, C., L. Bannwarth, I. Oubella, D. Zuniga, A. Haouz, E. Forest, R. Scala, S. Bendahhou, R. De Zorzi, D. Perahia, and C. Vénien-Bryan. (2021). Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain. Int J Mol Sci 23:.

Fernandes, C.A.H., D. Zuniga, C. Fagnen, V. Kugler, R. Scala, G. Péhau-Arnaudet, R. Wagner, D. Perahia, S. Bendahhou, and C. Vénien-Bryan. (2022). Cryo-electron microscopy unveils unique structural features of the human Kir2.1 channel. Sci Adv 8: eabq8489.

Fernandes, M.A., M.S. Santos, A.J. Moreno, G. Duburs, C.R. Oliveira, and J.A. Vicente. (2004). Glibenclamide interferes with mitochondrial bioenergetics by inducing changes on membrane ion permeability. J Biochem Mol Toxicol 18: 162-169.

Flagg, T.P., F. Charpentier, J. Manning-Fox, M.S. Remedi, D. Enkvetchakul, A. Lopatin, J. Koster, and C. Nichols. (2004). Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels. Am. J. Physiol. Heart Circ Physiol 286: H1361-1369.

Fodstad, H., H. Swan, M. Auberson, I. Gautschi, J. Loffing, L. Schild, and K. Kontula. (2004). Loss-of-function mutations of the K+ channel gene KCNJ2 constitute a rare cause of long QT syndrome. J Mol. Cell Cardiol 37: 593-602.

Fürst, O., C.G. Nichols, G. Lamoureux, and N. D''Avanzo. (2014). Identification of a cholesterol-binding pocket in inward rectifier K+ (Kir) channels. Biophys. J. 107: 2786-2796.

Gao, J., J. Wang, Y. Han, Q. Deng, X. Wang, W. Cai, and Y. Chen. (2022). [Clinical characteristics and genetic analysis of an ethnic Han Chinese child with Keppen-Lubinsky syndrome due to a de novo KCNJ6 mutation]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 39: 35-38.

Garcia ML., Priest BT., Alonso-Galicia M., Zhou X., Felix JP., Brochu RM., Bailey T., Thomas-Fowlkes B., Liu J., Swensen A., Pai LY., Xiao J., Hernandez M., Hoagland K., Owens K., Tang H., de Jesus RK., Roy S., Kaczorowski GJ. and Pasternak A. (2014). Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis. J Pharmacol Exp Ther. 348(1):153-64.

Gazgalis, D., L. Cantwell, Y. Xu, G.A. Thakur, M. Cui, F. Guarnieri, and D.E. Logothetis. (2022). Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism. Int J Mol Sci 23:.

Glaaser, I.W. and P.A. Slesinger. (2015). Structural Insights into GIRK Channel Function. Int Rev Neurobiol 123: 117-160.

Hager, N.A., C.K. McAtee, M.A. Lesko, and A.F. O''Donnell. (2021). Inwardly Rectifying Potassium Channel Kir2.1 and its "Kir-ious" Regulation by Protein Trafficking and Roles in Development and Disease. Front Cell Dev Biol 9: 796136.

Haider, S., A.I. Tarasov, T.J. Craig, M.S. Sansom, and F.M. Ashcroft. (2007). Identification of the PIP2-binding site on Kir6.2 by molecular modelling and functional analysis. EMBO. J. 26: 3749-3759.

Hansen, S.B., X. Tao, and R. MacKinnon. (2011). Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477: 495-498.

Hill, C.E., M.M. Briggs, J. Liu, and L. Magtanong. (2002). Cloning, expression, and localization of a rat hepatocyte inwardly rectifying potassium channel. Am. J. Physiol. Gastrointest. Liver Physiol. 282: G233-G240.

Hille, B. (1992). Ionic Channels of Excitable Membranes, 2nd ed. Sinaur Associates, Inc., Sunderland, MA.

Ho, I.H.M. and R.D. Murrell-Lagnado. (1999). Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. J. Biol. Chem. 274: 8639-8648.

Huang, C.W. and C.C. Kuo. (2016). A synergistic blocking effect of Mg2+ and spermine on the inward rectifier K+ (Kir2.1) channel pore. Sci Rep 6: 21493.

Inanobe, A., A. Nakagawa, and Y. Kurachi. (2011). Interactions of cations with the cytoplasmic pores of inward rectifier K+ channels in the closed state. J. Biol. Chem. 286: 41801-41811.

Ishihara, K., T. Yamamoto, and Y. Kubo. (2009). Heteromeric assembly of inward rectifier channel subunit Kir2.1 with Kir3.1 and with Kir3.4. Biochem. Biophys. Res. Commun. 380: 832-837.

Jaroslawski, S., B. Zadek, F. Ashcroft, C. Venien-Bryan, and S. Scheuring. (2007). Direct visualization of KirBac3.1 potassium channel gating by atomic force microscopy. J. Mol. Biol. 374(2):500-505.

Jaudon, F., M. Albini, S. Ferroni, F. Benfenati, and F. Cesca. (2021). A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor. J Cell Sci. [Epub: Ahead of Print]

Jesus, R.L.C., I.L.P. Silva, F.A. Araújo, R.A. Moraes, L.B. Silva, D.S. Brito, G.B.C. Lima, Q.L. Alves, and D.F. Silva. (2022). 7-Hydroxycoumarin Induces Vasorelaxation in Animals with Essential Hypertension: Focus on Potassium Channels and Intracellular Ca Mobilization. Molecules 27:.

Kuo, A., J.M. Gulbis, J.F. Antcliff, T. Rahman, E.D. Lowe, J. Zimmer, J. Cuthbertson, F.M. Ashcroft, T. Ezaki, and D.A. Doyle. (2003). Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300: 1922-1926.

Kurata, H.T., M. Rapedius, M.J. Kleinman, T. Baukrowitz, and C.G. Nichols. (2010). Voltage-dependent gating in a "voltage sensor-less" ion channel. PLoS Biol 8: e1000315.

Kuß, J., B. Stallmeyer, M. Goldstein, S. Rinné, C. Pees, S. Zumhagen, G. Seebohm, N. Decher, L. Pott, M.C. Kienitz, and E. Schulze-Bahr. (2019). Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K Channel) Channel Function. Circ Genom Precis Med 12: e002238.

Leal-Pinto, E., Y. Gómez-Llorente, S. Sundaram, Q.Y. Tang, T. Ivanova-Nikolova, R. Mahajan, L. Baki, Z. Zhang, J. Chavez, I. Ubarretxena-Belandia, and D.E. Logothetis. (2010). Gating of a G protein-sensitive mammalian Kir3.1 prokaryotic Kir channel chimera in planar lipid bilayers. J. Biol. Chem. 285: 39790-39800.

Lee, A.G. (2020). Interfacial Binding Sites for Cholesterol on Kir, Kv, K, and Related Potassium Channels. Biophys. J. [Epub: Ahead of Print]

Li, D., T. Jin, D. Gazgalis, M. Cui, and D.E. Logothetis. (2019). On the mechanism of the GIRK2 channel gating by phosphatidylinositol bisphosphate (PIP2), sodium, and the Gβγ dimer. J. Biol. Chem. [Epub: Ahead of Print]

Li, J., C.F. Kline, T.J. Hund, M.E. Anderson, and P.J. Mohler. (2010). Ankyrin-B regulates Kir6.2 membrane expression and function in heart. J. Biol. Chem. 285: 28723-28730.

Li, J., Y. Li, Y. Liu, H. Yu, N. Xu, D. Huang, Y. Xue, S. Li, H. Chen, J. Liu, Q. Li, Y. Zhao, R. Zhang, H. Xue, Y. Sun, M. Li, P. Li, M. Liu, Z. Zhang, X. Li, W. Du, N. Wang, and B. Yang. (2021). Fibroblast Growth Factor 21 Ameliorates Na1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes. Front Pharmacol 12: 715466.

Lin, Y.W., J.D. Bushman, F.F. Yan, S. Haidar, C. Macmullen, A. Ganguly, C.A. Stanley, and S.L. Shyng. (2008). Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism. J. Biol. Chem. 283: 9146-9156.

Lyu, C., G.W. Lyu, J. Mulder, A. Martinez, and T.S. Shi. (2020). G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 is Upregulated in Rat DRGs and Spinal Cord After Peripheral Nerve Injury. J Pain Res 13: 419-429.

Ma, D., X.D. Tang, T.B. Rogers, and P.A. Welling. (2007). An Andersen-Tawil syndrome mutation in Kir2.1 (V302M) alters the G-loop cytoplasmic K+ conduction pathway. J. Biol. Chem. 282: 5781-5789.

Makary, S.M., T.W. Claydon, K.M. Dibb, and M.R. Boyett. (2006). Base of pore loop is important for rectification, activation, permeation, and block of Kir3.1/Kir3.4. Biophys. J. 90: 4018-4034.

Marmolejo-Murillo, L.G., I.A. Aréchiga-Figueroa, E.G. Moreno-Galindo, R.A. Navarro-Polanco, A.A. Rodríguez-Menchaca, M. Cui, J.A. Sánchez-Chapula, and T. Ferrer. (2017). Chloroquine blocks the Kir4.1 channels by an open-pore blocking mechanism. Eur J Pharmacol 800: 40-47.

Martin, G.M., B. Kandasamy, F. DiMaio, C. Yoshioka, and S.L. Shyng. (2017). Anti-diabetic drug binding site in a mammalian K channel revealed by Cryo-EM. Elife 6:.

Martin, G.M., C. Yoshioka, E.A. Rex, J.F. Fay, Q. Xie, M.R. Whorton, J.Z. Chen, and S.L. Shyng. (2017). Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating. Elife 6:. [Epub: Ahead of Print]

Matamoros, M. and C.G. Nichols. (2021). Pore-forming transmembrane domains control ion selectivity and selectivity filter conformation in the KirBac1.1 potassium channel. J Gen Physiol 153:.

Mathiharan, Y.K., I.W. Glaaser, Y. Zhao, M.J. Robertson, G. Skiniotis, and P.A. Slesinger. (2021). Structural insights into GIRK2 channel modulation by cholesterol and PIP. Cell Rep 36: 109619.

Meng, X.Y., H.X. Zhang, D.E. Logothetis, and M. Cui. (2012). The molecular mechanism by which PIP(2) opens the intracellular G-loop gate of a Kir3.1 channel. Biophys. J. 102: 2049-2059.

Meng, X.Y., S. Liu, M. Cui, R. Zhou, and D.E. Logothetis. (2016). The Molecular Mechanism of Opening the Helix Bundle Crossing (HBC) Gate of a Kir Channel. Sci Rep 6: 29399.

Minor, D.L., Jr., S.J. Masseling, Y.N. Jan, and L.Y. Jan. (1999). Transmembrane structure of an inwardly rectifying potassium channel. Cell 96: 879-891.

Morin, M., A.L. Forst, P. Pérez-Torre, A. Jiménez-Escrig, V. Barca-Tierno, E. García-Galloway, R. Warth, J.L. Lopez-Sendón Moreno, and M.A. Moreno-Pelayo. (2020). Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype. Neurogenetics. [Epub: Ahead of Print]

Ortiz, D. and J. Bryan. (2015). Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP. Front Endocrinol (Lausanne) 6: 48.

Partridge, C.J., D.J. Beech, and A. Sivaprasadarao. (2001). Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J. Biol. Chem. 276: 35947-35952.

Payne, J.E., A.V. Dubois, R.J. Ingram, S. Weldon, C.C. Taggart, J.S. Elborn, and M.M. Tunney. (2017). Activity of innate antimicrobial peptides and ivacaftor against clinical cystic fibrosis respiratory pathogens. Int J Antimicrob Agents 50: 427-435.

Pegan, S., C. Arrabit, W. Zhou, W. Kwiatkowski, A. Collins, P.A. Slesinger, and S. Choe. (2005). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci 8: 279-287.

Pratt, E.B. and S.L. Shyng. (2011). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity. Channels (Austin) 5: 314-319.

Principalli, M.A., J.P. Dupuis, C.J. Moreau, M. Vivaudou, and J. Revilloud. (2015). Kir6.2 activation by sulfonylurea receptors: a different mechanism of action for SUR1 and SUR2A subunits via the same residues. Physiol Rep 3:.

Rajabian, A., F. Rajabian, F. Babaei, M. Mirzababaei, M. Nassiri-Asl, and H. Hosseinzadeh. (2022). Interaction of Medicinal Plants and Their Active Constituents With Potassium Ion Channels: A Systematic Review. Front Pharmacol 13: 831963.

Rapedius, M., S. Haider, K.F. Browne, L. Shang, M.S. Sansom, T. Baukrowitz, and S.J. Tucker. (2006). Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel. EMBO Rep 7: 611-616.

Raphemot, R., T.Y. Estévez-Lao, M.F. Rouhier, P.M. Piermarini, J.S. Denton, and J.F. Hillyer. (2014). Molecular and functional characterization of Anopheles gambiae inward rectifier potassium (Kir1) channels: a novel role in egg production. Insect Biochem Mol Biol 51: 10-19.

Remedi, M.S., J.B. Friedman, and C.G. Nichols. (2017). Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel. J Gen Physiol 149: 75-84.

Rodríguez-Menchaca, A.A., R.A. Navarro-Polanco, T. Ferrer-Villada, J. Rupp, F.B. Sachse, M. Tristani-Firouzi, and J.A. Sánchez-Chapula. (2008). The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel. Proc. Natl. Acad. Sci. U.S.A. 105: 1364-1368.

Rodríguez-Menchaca, A.A., I.A. Aréchiga-Figueroa, and J.A. Sánchez-Chapula. (2016). The molecular basis of chloroethylclonidine block of inward rectifier (Kir2.1 and Kir4.1) K+ channels. Pharmacol Rep 68: 383-389.

Rosenhouse-Dantsker, A. (2018). Cholesterol-Binding Sites in GIRK Channels: The Devil is in the Details. Lipid Insights 11: 1178635317754071.

Rosenhouse-Dantsker, A. (2019). Cholesterol Binding Sites in Inwardly Rectifying Potassium Channels. Adv Exp Med Biol 1135: 119-138.

Rufino, A.T., S.C. Rosa, F. Judas, A. Mobasheri, M.C. Lopes, and A.F. Mendes. (2013). Expression and function of K(ATP) channels in normal and osteoarthritic human chondrocytes: Possible role in glucose sensing. J. Cell. Biochem. 114: 1879-1889.

Ruknudin, A., D.H. Schulze, S.K. Sullivan, W.J. Lederer, and P.A. Welling. (1998). Novel subunit composition of a renal epithelial KATP channel. J. Biol. Chem. 273: 14165-14171.

Sackin, H., M. Nanazashvili, L.G. Palmer, M. Krambis, and D.E. Walters. (2005). Structural locus of the pH gate in the Kir1.1 inward rectifier channel. Biophys. J. 88: 2597-2606.

Saito, T., T. Sato, T. Miki, S. Seino, and H. Nakaya. (2005). Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am. J. Physiol. Heart Circ Physiol 288: H352-357.

Salkoff, L. and T. Jegla. (1995). Surfing the DNA databases for K+ channels nets yet more diversity. Neuron 15: 489-492.

Seino, S. (1999). ATP-sensitive potassium channels: a model of heteromultimeric potassium channel-receptor assemblies. Annu. Rev. Physiol. 61: 337-362.

Shibata, M., E. Ishizaki, T. Zhang, M. Fukumoto, A. Barajas-Espinosa, T. Li, and D.G. Puro. (2018). Purinergic Vasotoxicity: Role of the Pore/Oxidant/K Channel/Ca Pathway in P2X-Induced Cell Death in Retinal Capillaries. Vision (Basel) 2:.

Shin, H.G. and Z. Lu. (2005). Mechanism of the voltage sensitivity of IRK1 inward-rectifier K+ channel block by the polyamine spermine. J Gen Physiol 125: 413-426.

Shuck, M.E., J.H. Bock, C.W. Benjamin, T.D. Tsai, K.S. Lee, J.L. Slightom, and M.J. Bienkowski. (1994). Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel. J. Biol. Chem. 269: 24261-24270.

Sun, W., T. Li, H. Ma, S. Lin, M. Xie, Y. Luo, R. Tian, and S. Tang. (2019). The effect of K+ channel opener pinacidil on the transmembrane potassi channel protein kir4.1 of retinal müller cells in vitro and diabetic rats. Panminerva Med. [Epub: Ahead of Print]

Sung, M.W., C.M. Driggers, B. Mostofian, J.D. Russo, B.L. Patton, D.M. Zuckerman, and S.L. Shyng. (2022). Ligand-mediated Structural Dynamics of a Mammalian Pancreatic K Channel. J. Mol. Biol. 434: 167789.

Suzuki, Y., M. Itakura, M. Kashiwagi, N. Nakamura, T. Matsuki, H. Sakuta, N. Naito, K. Takano, T. Fujita, and S. Hirose. (1999). Identification by differential display of a hypertonicity-inducible inward rectifier potassium channel highly expressed in chloride cells. J. Biol. Chem. 274: 11376-11382.

Tammaro, P. and F.M. Ashcroft. (2007). A mutation in the ATP-binding site of the Kir6.2 subunit of the KATP channel alters coupling with the SUR2A subunit. J. Physiol. 584: 743-753.

Tanemoto, M., T. Abe, S. Uchida, and K. Kawahara. (2014). Mislocalization of K+ channels causes the renal salt wasting in EAST/SeSAME syndrome. FEBS Lett. 588: 899-905.

Tao, X., J.L. Avalos, J. Chen, and R. MacKinnon. (2009). Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 Å resolution. Science 326: 1668-1674.

Toms, M., A.M. Dubis, W.S. Lim, A.R. Webster, M.B. Gorin, and M. Moosajee. (2019). Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish. Exp Eye Res 189: 107852.

Töpert, C., F. Döring, E. Wischmeyer, C. Karschin, J. Brockhaus, K. Ballanyi, C. Derst, and A. Karschin. (1998). Kir2.4: a novel K+ inward rectifier channel associated with motoneurons of cranial nerve nuclei. J. Neurosci. 18: 4096-4105.

Tselnicker, I. and N. Dascal. (2010). Further characterization of regulation of Ca(V)2.2 by stargazin. Channels (Austin) 4: 351-354.

Usher, S.G., F.M. Ashcroft, and M.C. Puljung. (2021). Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time. J Vis Exp.

Vera, E., I. Cornejo, J. Burgos, M.I. Niemeyer, F.V. Sepúlveda, and L.P. Cid. (2019). A novel Kir7.1 splice variant expressed in various mouse tissues shares organisational and functional properties with human leber amaurosis-causing mutations of this K channel. Biochem. Biophys. Res. Commun. [Epub: Ahead of Print]

Wang S., Makhina EN., Masia R., Hyrc KL., Formanack ML. and Nichols CG. (2013). Domain organization of the ATP-sensitive potassium channel complex examined by fluorescence resonance energy transfer. J Biol Chem. 288(6):4378-88.

Weng, J., A. Wang, D. Zhang, C. Liao, and G. Li. (2021). A double bilayer to study the nonequilibrium environmental response of GIRK2 in complex states. Phys Chem Chem Phys 23: 15784-15795.

Wu, X.Y. and X.Y. Yu. (2019). Overexpression of KCNJ4 correlates with cancer progression and unfavorable prognosis in lung adenocarcinoma. J Biochem Mol Toxicol 33: e22270.

Xie, L.H., S.A. John, B. Ribalet, and J.N. Weiss. (2005). Long polyamines act as cofactors in PIP2 activation of inward rectifier potassium (Kir2.1) channels. J Gen Physiol 126: 541-549.

Yan, F.F., Y.W. Lin, C. MacMullen, A. Ganguly, C.A. Stanley, and S.L. Shyng. (2007). Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue. Diabetes 56: 2339-2348.

Yang, Y., W. Shi, X. Chen, N. Cui, A.S. Konduru, Y. Shi, T.C. Trower, S. Zhang, and C. Jiang. (2011). Molecular basis and structural insight of vascular K(ATP) channel gating by S-glutathionylation. J. Biol. Chem. 286: 9298-9307.

Yokogawa, M., M. Osawa, K. Takeuchi, Y. Mase, and I. Shimada. (2011). NMR analyses of the Gbetagamma binding and conformational rearrangements of the cytoplasmic pore of G protein-activated inwardly rectifying potassium channel 1 (GIRK1). J. Biol. Chem. 286: 2215-2223.

Zangerl-Plessl, E.M., M. Qile, M. Bloothooft, A. Stary-Weinzinger, and M.A.G. van der Heyden. (2019). Disease Associated Mutations in K Proteins Linked to Aberrant Inward Rectifier Channel Trafficking. Biomolecules 9:.

Zeng, W.-Z., X.-J. Li, D.W. Hilgemann, and C.-L. Huang. (2003). Protein kinase C inhibits ROMK1 channel activity via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. J. Biol. Chem. 278: 16852-16856.

Zhang, B., Y. Jin, L. Zhang, H. Wang, and X. Wang. (2022). Pentamidine Ninety Years on: the Development and Applications of Pentamidine and its Analogs. Curr. Med. Chem. [Epub: Ahead of Print]

Zhang, C., T. Miki, T. Shibasaki, M. Yokokura, A. Saraya, and S. Seino. (2005). Identification and characterization of a novel member of the ATP-sensitive K+ channel subunit family, Kir6.3, in zebrafish. Physiol Genomics. 24: 290-297.

Zhang, W., P. Das, S. Kelangi, and M. Bei. (2020). Potassium channels as potential drug targets for limb wound repair and regeneration. Precis Clin Med 3: 22-33.

Zhao, Z., G. Liu, H. Zhang, P. Ruan, J. Ge, and Q. Liu. (2021). BIRC5, GAJ5, and lncRNA NPHP3-AS1 Are Correlated with the Development of Atrial Fibrillation-Valvular Heart Disease. Int Heart J 62: 153-161.

Zhou, Q., E.B. Pratt, and S.L. Shyng. (2013). Engineered Kir6.2 mutations that correct the trafficking defect of K(ATP) channels caused by specific SUR1 mutations. Channels (Austin) 7: 313-317.


TC#NameOrganismal TypeExample

ATP-activated inward rectifier K+ channel, IRK1 (also called ROMK or KIR1.1) (regulated by Sur1, allowing ATP sensitivity; also activated by phosphatidylinositol 4,5-bisphosphate (PIP) with affinity to PIP controlled by protein kinase A phosphorylation (which increases affinity for PIP) and protein kinase C phosphorylation (which decreases affinity for PIP (Zeng et al., 2003). The mechanism of voltage sensitivity of IRK1 inward-rectifier K+ channel block by the polyamine, spermine, has been proposed (Shin and Lu 2005). A putative pH sensor has been identified (Rapedius et al. 2006). Closure of the Kir1.1 pH gate results from steric occlusion of the permeation path by the convergence of four leucines (or phenylalanines) at the cytoplasmic apex of the inner transmembrane helices. In the open state, K+ crosses the pH gate together with its hydration shell (Sackin et al. 2005). Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide, causes loss of cell viability by inducing apoptosis. AOH-induced apoptosis through a mitochondria-dependent pathway is characterized by p53 activation, an opening of the mitochondrial permeability transition pore (PTP), loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O2- and caspase 9 and 3 activation (Bensassi et al., 2012). Pharmacological inhibition of renal ROMK causes diuresis and natriuresis in the absence of kaliuresis (Garcia et al. 2013). Cholesterol binding sites in KIR channels have been identified (Rosenhouse-Dantsker 2019). The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Disease-associated mutations in KIR proteins have been linked to aberrant inward rectifier channel trafficking (Zangerl-Plessl et al. 2019). Interfacial binding Ssites for cholesterol on Kir, Kv, K2P, and related potassium channels have been identified (Lee 2020). Decreasing pH(in) increases the sensitivity of ROMK2 channels to K+(out) by altering the properties of the selectivity filter (Dahlmann et al. 2004).


IRK1 of Homo sapiens (P48048)


G-protein-activated inward rectifying K+ channel, Kir3.2, KATP2, KCNJ6, KCNJ7 or GIRK2 of 423 aas and 2 TMSs (Inanobe et al., 2011; Yokogawa et al. 2011). Mutations cause the Keppen-Lubinsky syndrome (Gao et al. 2022). It functions in electrical signaling in neurons and muscle cells (Weng et al. 2021), being important in regulating heart rate and neuronal excitability.  It is activated by binding of the βγ-subunit complex to the cytoplasmic pore gate (Yokogawa et al. 2011). Chen et al. 2017 found that GIRK channels are activated by Ivermectin (IVM). Cholesterol binds to and upregulates GIRK channels (GIRK2 and 4), and the binding sites have been determined (Rosenhouse-Dantsker 2018). An inherited gain-of-function mutation in the human GIRK3.4 causes familial human sinus node dysfunction (SND). The increased activity of GIRK channels likely leads to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate (Kuß et al. 2019). GIRK2 channels are abundantly expressed in the heart and require that phosphatidylinositol bisphosphate (PIP2) is present so that intracellular channel-gating regulators such as Gbetagamma (Gβγ) and Na+ ions maintain the channel-open state. Li et al. 2019 determined how each regulator uses  channel domain movements to control gate transitions. Na+ controls the cytosolic gate of the channel through an anti-clockwise rotation, whereas Gβγ stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects altered the way by which the channel interacts with PIP2 and thereby stabilizes the open states of the respective gates (Li et al. 2019). The protein plays a role in heart atrial fibrillation-valvular heart disease (VHD) (Zhao et al. 2021). Measurements of ligand binding and channel current have been made (Usher et al. 2021). CryoEM structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) and phosphatidylinositol 4,5-bisphosphate (PIP2) reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain, suggesting that CHS stabilizes the PIP2 interaction with the channel to promote engagement of the cytoplasmic domain with the transmembrane region (Mathiharan et al. 2021).


Kir3.2 of Homo sapiens (P48051)


Inward rectifying potassium channel 16, Kir5.1 or KCNJ16. (Potassium channel subfamily J member 16).  Involved in pH and fluid regulation.  Forms heteromers with Kir4.1/KCNJ10 or Kir2.1/KCNJ2. MAGI-1 anchors Kir4.1 channels (Kir4.1 homomer and Kir4.1/Kir5.1 heteromer) and contributes to basolateral K+ recycling. The Kir4.1 A167V mutation is associated with EAST/SeSAME syndrome caused by mistrafficking of the mutant channels and inhibiting their expression on the basolateral surface of tubular cells. These findings suggest that mislocalization of the Kir4.1 channels contributes to renal salt wasting. (Tanemoto et al. 2014).


KCNJ16 of Homo sapiens


G protein-activated inward rectifying K+ channel 1 (Kir3.1; IRK3; KCNJ3; GIRK1). Regulates the heartbeat in humans. Phosphatidylinositol bisphosphate (PIP2) activates by opening the intracelluar G-loop gate (Meng et al., 2012).  Along the ion permeation pathway, three relatively narrow regions (the selectivity filter, the inner helix bundle crossing, and the cytosolic G loop) may serve as gates to control ion permeation (Meng et al. 2016). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). Changes in the levels of cholesterol and PI(4,5)P2 may act in concert to provide fine-tuning of Kir3 channel function (Bukiya et al. 2017). Kir3.1 forms oligomers with Kir3.4 (TC# 1.A.2.1.3) and transporters Rb+ and spermine.  It has been suggested that the selectivity filter is responsible for inward rectification and agonist activation as well as permeation and block (Makary et al. 2006). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (Pegan et al. 2005). A key basic residue that coordinates PIP2 to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state (Gazgalis et al. 2022).


Kir3.1 (IRK3) of Homo sapiens (P48549)


ATP-sensitive inward rectifying K+ channel 8, KCNJ8 or Kir6.1. It acts with Sur2B (3.A.1.208.23). Channel activity is inhibited in oxidative stress via S-glutathionylation (Yang et al., 2011). Oxidative sensitivity is dependent on Cys176 (Yang et al., 2011).  These proteins comprise part of a glucose sensing mechanism (Rufino et al. 2013). It may play a role in limb wound repair and regeneration (Zhang et al. 2020). It is inhibited by glibenclamide (glyburide), an antidiabetic sulfonylurea used in the treatment of type II diabetes (Fernandes et al. 2004). Gain-of-function mutations in Kir6.1 and regulatory (SUR1) subunits of KATP channels can cause human neonatal diabetes mellitus by altering insulin secretion (Remedi et al. 2017).


Kir6.1 of Homo sapiens (Q15842)


Inward rectifying potassium (K+) (IRK) channel of 426 aas and 2 TMSs, AgaP.

AgaP of Anopheles gambiae (African malaria mosquito)


Kir1 (AgaP) K+ channel of 444 aas and 2 TMSs. Kir channels play a role in mosquito fecundity and may be promising molecular targets for the development of a new class of mosquitocides (Raphemot et al. 2014).

Kir1 of Anopheles gambiae (African malaria mosquito)


Inward rectifying K+ channel, Kir4.1, encoded by the KCNJ10 gene, of 379 aas and 2 TMSs.  It is inhibited by chloroethylclonidine and pentamidine which bind in the channel (Rodríguez-Menchaca et al. 2016; Aréchiga-Figueroa et al. 2017). It is also inhibited by chloropuine which inhibits by an open pore blocking mecnanism (Marmolejo-Murillo et al. 2017). Loss-of-function mutations in the pore-forming Kir4.1 subunit cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (SeSAME/EST syndrome) Pentamidine potently inhibited Kir4.1 channels when applied to the cytoplasmic side under inside-out patch clamp configuration (IC50 = 97nM). The block was voltage dependent. Molecular modeling predicted the binding of pentamidine to the transmembrane pore region of Kir4.1 at amino acids T127, T128 and E158. Mutation of each of these residues reduced the potency of pentamidine to block Kir4.1 channels (Aréchiga-Figueroa et al. 2017). Mutations in the KCNJ10 gene are associated with a distinctive ataxia, sensorineural hearing loss and a spasticity (Morin et al. 2020). It is regulated by kidins220 (TC# 8.A.28.1.8) (Jaudon et al. 2021). Pentamidine is a potent inhibitor of Kir4.1 (Zhang et al. 2022).

Kir4.1 of Homo sapiens


KCNJ11 or Kir6.2 or KATP of 390 aas; 96% identical to the rat homologue, TC# 1.A.2.1.7. Congenital hyperinsulinism (CHI) is characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K+ (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Many studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide (Yan et al. 2007). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (Tammaro and Ashcroft 2007). Kir6.2 is an ATP-sensitive potassium (KATP) channel coupling cell metabolism to electrical activity by regulating K+ fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP2), which binds to Kir6.2 and reduces channel inhibition by ATP.  The PIP2 binding site has been identified (Haider et al. 2007).  KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic beta-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Martin et al. 2017 used cryo-EM to elucidate the structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea, glibenclamide, at ~6 Å resolution, revealed a closed Kir6.2 tetrameric core with four peripheral SUR1s, each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest that SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity (Martin et al. 2017). a cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug glibenclamide and ATP has been solved at 3.63 Å resolution. The structure shows that glibenclamide is lodged in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer (Martin et al. 2017). The activation of K(ATP) channels contributes to the shortening of action potential duration but is not the primary cause of extracellular K+ accumulation during early myocardial ischemia (Saito et al. 2005). KATP binds nucleotides (Usher et al. 2021). Mitochondrial KATP channels stabilize intracellular Ca2+ during hypoxia in retinal horizontal cells of goldfish (Carassius auratus) (Country and Jonz 2021). Medicinal plant products can interact with KATP (Rajabian et al. 2022). Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels has been observed (Flagg et al. 2004). Thus, a compensatory increase in I(Ca) counteracts a mild activation of ATP-insensitive K(ATP) channels. Pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain, while depleting one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformational change remodels a network of intra- and inter-subunit interactions as well as the ATP and PIP2 binding pockets. The structures resolved key contacts between the distal N-terminus of Kir6.2 and SUR1's ABC module involving residues implicated in channel function and showed a SUR1 residue, K134, participates in PIP2 binding. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP2 binding, suggesting a mechanism for competitive gating by ATP and PIP2 (Sung et al. 2022). The natural product, 7-hydroxycoumarin (7-HC), exhibits pharmacological properties linked to antihypertensive mechanisms of action. This relaxant effect induced by 7-HC relies on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors) (Jesus et al. 2022).

Kir6.2 or KATP of Homo sapiens


Inward rectifier potassium channel 4, KCNJ4, IRK3 or 4, of 445 aas. Its voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium, and it can be blocked by extracellular barium and cesium. It may play a role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium. Overexpression of KCNJ4 correlates with cancer progression and nfavorable prognosis in lung adenocarcinoma (Wu and Yu 2019).


KMCJ4 of Homo sapiens


G protein-activated inward rectifier potassium channel 3, GIRK3 or KCNJ9 of 393 aas and 2 TMSs. It is expressed in sensory neurons and spinal cord and has uses both anterograde and retrograde axonal transport (Lyu et al. 2020).

GIRK3 of Homo sapiens


G-protein enhanced inward rectifier K channel 2, IRK1, IRK2, KCNJ2, KCNJ5, Kir2.1 (Andersen-Tawil Syndrome (ATS-1) protein; the V302M mutation causing the syndrome, alters the G-loop cytoplasmic K conduction pathway) (Bendahhou et al., 2003; Ma et al., 2007). (Blocked by chloroquine which binds in the cytoplasmic pore domain (Rodriguez-Menchaca et al., 2008)). Forms heteromultimers with Kir3.1 and Kir3.4 (Ishihara et al., 2009). A C-terminal domain is critical for the sensitivity of Kir2.1 to cholesterol (Epshtein et al., 2009). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification (Caballero et al., 2010).  The inhibitory cholesterol binding site has been identified (Fürst et al. 2014).  Polyamines and Mg2+ block ion flux synergistically (Huang and Kuo 2016). Long polyamines serve a dual role as both blockers and coactivators (with PIP2) of Kir2.1 channels (Xie et al. 2005).  Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification (Pegan et al. 2005). Loss-of-function mutations are a rare cause of long QT syndrome (Fodstad et al. 2004). Fibroblast growth factor 21 ameliorates NaV1.5 and Kir2.1 channel dysregulation in human AC16 cardiomyocytes (Li et al. 2021). The trafficking of Kir2.1 and its role in development have been reviewed (Hager et al. 2021). Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces (Barbera et al. 2022). CryoEM studies have revealed a well-connected network of interactions between the PIP2-binding site and the G-loop through residues R312 and H221.Moreover, the intrinsic tendency of the CTD to tether to the TMD and a movement of the secondary anionic binding site to the membrane even without PIP2 was revealed (Fernandes et al. 2022). The results revealed structural features unique to human Kir2.1.



IRK2 of Homo sapiens (P63252)


G-protein activated IRK5 (Kir3.4, KCNJ5, GIRK4) channel. The p75 neurotrophin receptor mediates cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate (Coulson et al., 2008). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). It forms an oligomeric channel with Kir3.1, transporting K+, Rb+ and spermine.  The selectivity filter may be responsible for inward rectification and agonist activation as well as permeation and block by Cs+ (Makary et al. 2006). Ivermictin activates GIRK channels in a PIP2-dependent manner (Chen et al. 2017). GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers (Cui et al. 2022). Activators, such as ML297, ivermectin, and GAT1508, activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. VU0529331 was the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 homomeric channels. The first highly selective small-molecule activator targeting GIRK4 homomeric channels is 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. The binding site of 3hi2one-G4 is formed by TMSs 1 and 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site; it causes channel activation by strengthening channel-phosphatidylinositol-4,5-bisphosphate interactions. Slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2 is a major determinant of isoform-specific selectivity (Cui et al. 2022).


IRK5 or GIRK4 of Homo sapiens (P48544)


Hepatocyte basolateral inwardly rectifying K+ channel, Kir4.2, involved in bile secretion (Hill et al., 2002).  This protein is 96% identical to the human KCNJ14 or KCNJ15 of 375 aas (Q99712).


Kir4.2 of Rattus norvegicus (Q91ZF1)


Cranial nerve inward rectifying K+ channel, Kir2.4 (IRK4) (Töpert et al., 1998).  The human ortholog, of 436 aas, is 94% identical and is called KCMJ14 or IRK4.


Kir2.4 of Rattus norvegicus (O70596)

1.A.2.1.6ATP-sensitive K+ channel, Kir6.3 (Zhang et al., 2005)AnimalsKir6.3 of Danio rerio (Q5R205)

Kidney/pancreas/muscle ATP-senstive, ER/Golgi K+ channel, KATP or ROMK (Kir6.2) (Boim et al., 1995) (three alternatively spliced isoforms are called ROMK1-3). Involved in congenital hyperinsulinism (Lin et al., 2008). Regulated by Ankyrin-B (Li et al., 2010). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 (SUR1) and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). This channel protects the myocardium from hypertrophy induced by pressure-overloading (Alvin et al., 2011). Domain organization studies show which domains in Sur and Kir6.2 interact (Wang et al. 2012).  KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion in pancreatic beta cells, and mutations in the former protein can compensate for mutations in the latter (Zhou et al. 2013).  Mutations cause inactivation of channel function by disrupting PIP2-dependent gating (Bushman et al. 2013). Thus, these proteins comprise part of the glucose sensing mechanism (Rufino et al. 2013).  A single point mutation can confer voltage sensitivity (Kurata et al. 2010).  Its involvement in type II diabetes has been reviewed by Bonfanti et al. 2015. KATP channels (Kir6.2/SUR1) in the brain and endocrine pancreas  couple metabolic status to the membrane potential. In beta-cells, increases in cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively.  Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations.  Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015).  Kir6.2 can associate with either SUR1 (TC# 3.A.1.208.4) or SUR2A (TC# 3.A.1.208.23) to form heteroctamers, leading to different locations and consequences (Principalli et al. 2015). IATP channels and Ca2+ influx play roles in purinergic vasotoxicity and cell death (Shibata et al. 2018).
       A cryo-EM structure of a hamster SUR1/rat Kir6.2 channel bound to a high-affinity sulfonylurea drug, glibenclamide, and ATP at 3.63 A resolution revealed details of the ATP and glibenclamide binding sites (Martin et al. 2017). The structure showed that glibenclamide lodges in the transmembrane bundle of the SUR1-ABC core connected to the first nucleotide binding domain near the inner leaflet of the lipid bilayer. Mutation of residues predicted to interact with glibenclamide led to reduced sensitivity to this drug (Martin et al. 2017).


ROMK of Rattus norvegicus (P70673)


The inward rectifier potassium channel 13, Kir 7.1, Kir1.4, or KCNJ13, of 360 aas and 2 TMSs. A splice variant expressed in mouse tissues shares organisational and functional properties with human leber amaurosis-causing mutations of this channel (Vera et al. 2019). In fact, mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD) (Toms et al. 2019). Pinacidil is a channel opener (Sun et al. 2019). It may play a role in the control of polyamine-mediated channel gating and in the blocking by intracellular magnesium. A Kir7.1 disease mutant T153I within the inner pore affects K+ conduction (Beverley et al. 2022).



Kir 7.1 or KCNJ13 of Homo sapiens (O60928)


The inward-rectifier K+ channel, Kir2.2, KCNJ12, KCNJN1, KCNJ18, IRK2, of 433 aas and 2 TMSs. The 3-d structure at 3.1 Å resolution is available (Tao et al., 2009). (It is 70% identical to Kir2.1 (TC # 1.A.2.1.2)). The structural basis of PIP2 activation of Kir2.2 has been presented (Hansen et al., 2011).


Kir2.2 of Homo sapiens (Q14500)


TC#NameOrganismal TypeExample

Prokaryotic K+-selective Kir channel KirBac1.1 (selectivity: K+ = Rb+ = Cs+ >> Li+, Na+ or NMGM) (Enkvetchakul et al., 2004), inward rectifying (Cheng et al., 2009). Closure of the Kir1.1 pH gate results from steric occlusion of the permeation path by the convergence of four leucines (or phenylalanines) at the cytoplasmic apex of the inner transmembrane helices. In the open state, K+ crosses the pH gate together with its hydration shell (Sackin et al. 2005). An inhibitory cholesterol binding site has been identified (Fürst et al. 2014). Conformational changes associated with an open activation gate have been identified, and these suggest an allosteric pathway that ties the selectivity filter to the activation gate through interactions between both transmembrane helices, the turret, the selectivity filter loop, and the pore helix. Specific residues involved in this conformational exchange that are highly conserved among human Kir channels have also been identified (Amani et al. 2020). Anionic lipids, especially cardiolipin, initiate a concerted rotation of the cytoplasmic domain subunits. This action buries ionic side chains away from the bulk water, while allowing water greater access to the K+ conduction pathway (Borcik et al. 2020). Kv1.5 channels are regulated by PKC-mediated endocytic degradation (Du et al. 2021). Pore-forming TMSs control ion selectivity and the selectivity filter conformation in the KirBac1.1 channel (Matamoros and Nichols 2021).


KirBac1.1 OF Burkholderia pseudomallei (IP7BA; gi33357898)


The KirBac3.1 K+ channel (a dimer of dimers with gating visualized by atomic force microscopy (Jaroslawski et al., 2007) (regulated by binding lipids, G-proteins, nucleotides, and ions (H+, Ca2+, and Mg2+)). The 3-D structure is available (1XL6_A).  The inhibitory cholesterol binding site has been identified (Fürst et al. 2014). The constricted opening in this, and presumably other, Kir channels does not impede potassium conduction (Black et al. 2020). The structural and dynamic properties of a KirBac3.1 mutant revealed the function of a highly conserved tryptophan in the transmembrane domain (Fagnen et al. 2021).


KirBac3.1 of Magnetospirillum magnetotacticum  (D9N164)


ATP-sensitive inward rectifying Kir K channel (Choi et al. 2010).


Kir K+ channel of Chromobacterium violaceum


Putative K+ channel


K+ channel of Synechocystis PCC 6803

Inward rectifier potassium channel 


K+ channel of Burkholderia xenovorans


Uncharacterized algal protein of 886 aas, largely hydrophilic with a VIC-type 2 TMS channel domain near its C-terminus.

UP of Klebsormidium nitens