8.A.5 The Voltage-gated K⁺ Channel β-subunit (Kvβ) Family Many β-subunits of voltage-gated K⁺ channels (VIC superfamily, TC #1.A.1.2.1-3) have been sequenced and functionally characterized. The one from rat has been crystallized, and a 2.1 Å resolution structure is available (Gulbis, 2000). The mammalian β-subunits are 350-410 residues in length. They exhibit extensive sequence similarity with many ubiquitous oxidoreductases, with bacterial stress response proteins and with plant auxin-induced proteins. These β-subunits are to some extent interchangeable, and a variety of alternative splice variants are found. They regulate various aspects of the voltage-gated mammalian channels as well as the Drosophila Shaker K⁺ channel. Thus they affect the voltage-dependence of the activation process, the rate of deactivation and both N-type and C-type inactivation. The conserved C-terminal domain of the β-subunit interacts with the conserved N-terminal hydrophilic domain of the Shaker α-subunit, the same region that determines the compatibility of α-subunits. The hyperkinetic gene of Drosophila encodes a β-subunit of 546 amino acyl residues that when defective produces the Shaker-like, ether-sensitive leg shaking. Regulatory β-subunits of other channel proteins of the VIC superfamily (TC #1.A.1) function in distinct regulatory capacities, and some are non-homologous to members of the Kvβ family. Myocardial blood flow is control by oxygen-sensing vascular Kvbeta proteins (Ohanyan et al. 2021).
References:
Accili, E.A., Y.A. Kuryshev, B.A. Wible, and A.M. Brown. (1998). Separable effects of human Kvbeta1.2 N- and C-termini on inactivation and expression of human Kv1.4. J. Physiol. 512(Pt2): 325-336.
Gulbis, J.M., M. Zhou, S. Mann, and R. MacKinnon. (2000). Structure of the cytoplasmic β subunit-T1 assembly of voltage-dependent K⁺ channels. Science 289: 123-127.
Jan, L.Y. and Y.N. Jan. (1997). Cloned potassium channels from eukaryotes and prokaryotes. Annu. Rev. Neurosci. 20: 91-123.
Mangubat, E.Z., T.-T. Tseng, and E. Jakobsson. (2003). Phylogenetic analyses of potassium channel auxiliary subunits. J. Mol. Microbiol. Biotechnol. (in press).
Ohanyan, V., S.M. Raph, M.M. Dwenger, X. Hu, T. Pucci, G.D. Mack, J.B. Moore Iv, W.M. Chilian, A. Bhatnagar, and M.A. Nystoriak. (2021). Myocardial Blood Flow Control by Oxygen Sensing Vascular Kvβ Proteins. Circ Res. [Epub: Ahead of Print]
Peters, C.J., M. Vaid, A.J. Horne, D. Fedida, and E.A. Accili. (2009). The molecular basis for the actions of KVbeta1.2 on the opening and closing of the KV1.2 delayed rectifier channel. Channels (Austin) 3: 314-322.
Tipparaju, S.M., S.Q. Liu, O.A. Barski, and A. Bhatnagar. (2007). NADPH binding to β-subunit regulates inactivation of voltage-gated K⁺ channels. Biochem. Biophys. Res. Commun. 359: 269-276.
Wang, W., J. Huang, Y. Hu, J. Feng, D. Gao, W. Fang, M. Xu, C. Ma, Z. Fu, Q. Chen, X. Liang, and J. Lu. (2024). Seascapes Shaped the Local Adaptation and Population Structure of South China Coast Yellowfin Seabream (Acanthopagrus latus). Mar Biotechnol (NY) 26: 60-73.
Examples:
TC#	Name	Organismal Type	Example
8.A.5.1.1	K⁺ channel β1a chain. Functions with Kv1.2 (Kvα1;KCNA2; TC# 1.A.1.2.10) to promote fast inactivation (Peters et al. 2009). Mediates closure of delayed rectifier potassium channels by physically obstructing the pore via its N-terminal domain and increases the speed of channel closure for other family members (Accili et al. 1998). Promotes the closure of KCNA1, KCNA2 and KCNA5 channels Accelerates the closure of heteromeric channels formed by KCNA1, KCNA2, KCNA4, KCNA5 and KCNA6. Binds NADPH as is required for efficient down-regulation of potassium channel activity (Tipparaju et al. 2007). The protein has NADPH-dependent aldoketoreductase activity, and oxidation of the bound NADPH decreases N-type inactivation of channel activity.	Mammals	*K⁺ channel subunit β1a of Homo sapiens* (Q14722)**

8.A.5.1.2	The hyperkinetic (Hk) protein	Animals	*Hk of Drosophila melanogaster* (Q24052)**

8.A.5.1.3	Chain A, β-subunit of 353 aas and possibly 3 C-terminal TMSs. The x-ray structure is available for this protein. The Kcnab2 ortholog in Danio rerio (Zebrafish) (Brachdanio rerio) (XP_009304567.1) is 85% identical to the rat homolog. It belongs to the shaker potassium channel beta subunit family. Genome analysis revealed that genetic structure is influenced by a variety of factors including salinity gradients, habitat distance, and ocean currents (Wang et al. 2024).	Animals	*β1a of Rattus norvegicus* (P63144)**

8.A.5.1.4	General stress protein 69, GSP69. There is no evidence that this protein functions to regulate a transport system in bacteria.	Bacteria	GSP69 of Bacillus subtilis

8.A.5.1.5	Aldo/keto (NADH) reductase of 346 aas, Tas. There is no evidence that this protein functions to regulate a transport system in bacteria.		Tas of E. coli

8.A.5.1.6	Uncharacterized oxidoreductase of 342 aas, YajO. There is no evidence that this protein functions to regulate a transport system in bacteria.		YajO of E. coli

8.A.5.1.7	Oxidoreductase, YdhF, of 298 aas and 0 TMSs. Not known to be involved in transport.		YdhF of E. coli