8.A.16.2.1
Transmembrane AMPA receptor (AMPAR) regulatory proteins, also called voltage-dependent Ca²⁺ channel γ2 subunits, TARPγ2, CACNG2, gamma-2 or Stargazin; regulate Ca(v)2.2 (TC# 1.A.1.11.19) as well as GIRK (TC# 1.A.2.1.3) (Tselnicker and Dascal 2010). TARPγ2 and TARPγ7 (8.A.16.2.5) can substitute for each other (Yamazaki et al. 2015).  TARPs also enhance AMPAR function, altering ligand efficacy and receptor gating kinetics and shaping the postsynaptic response. Stargazin rescues gating deficiencies in AMPARs carrying mutations that destabilize the closed-cleft states of the ligand-binding domain (LBD), suggesting that stargazin stabilizes closed LBD states (MacLean et al. 2014).  For Ca²⁺-permeable AMPARs, stargazin enhances receptor function by increasing single-channel conductance, slowing channel gating, increasing calcium permeability, and relieving the voltage-dependent block by endogenous intracellular polyamines (McGee et al. 2015).  TARPs alter the conformations of pore-forming subunits and thereby affect antagonist interactions (Cokić and Stein 2008). By shifting the balance between AMPAR activation and desensitization, TARPs markedly facilitate the transduction of spillover-mediated synaptic signaling (Coombs et al. 2017). Stargazin plays a role in AMPA receptor trafficking through the early compartments of the biosynthetic pathway (Vandenberghe et al. 2005). Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes form highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping (Zeng et al. 2019). Positive allosteric modulators (PAMs) of AMPA receptors boost cognitive performance in clinical studies, and mibampator and BIIB104 discriminate between AMPARs complexed with distinct TARPs, and particularly those with lower stargazin/gamma2 efficacy such as BIIB104 (Ishii et al. 2020). TARPs modulate receptor-mediated paired-pulse depression and recovery from desensitization (Devi et al. 2020).