Channelpedia

Cavγ2

Description: calcium channel, voltage-dependent, gamma subunit 2
Gene: cacng2
Alias: cacng2

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Introduction

The second member of the calcium channel gamma subunit family, gamma2 (=CACNG2), was identified from genetic analysis of the stargazer mouse, an animal that displays a characteristic phenotype that includes head tossing and epileptic episodes (Noebels [1327]).

CACNG2 (also known as FLJ41437; MGC138502; MGC138504) encodes a type I transmembrane AMPA receptor regulatory protein (TARP), also known as a gamma2 subunit. TARPs regulate both trafficking and channel gating of the AMPA receptors. This gene is part of a functionally diverse eight-member protein subfamily of the PMP-22/EMP/MP20 family. This gene is a susceptibility locus for schizophrenia.

http://www.ncbi.nlm.nih.gov/gene/10369

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Gene

Phylogenetic analysis suggests that all c subunits evolved from a single ancestral gene through tandem repeat and chromosome duplication (Burgess [1312], Chu [1312]). Based on sequence homology and chromosomal linkage the c subunits can be divided into three clusters: (c1, c6), (c5, c7), and (c2, c3, c4, c8) (Burgess [1312], Chu [1312]).

Species NCBI gene ID Chromosome Position
Human 10369 22 142895
Mouse 12300 15 128301
Rat 84347 7 125678
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Transcript

Species NCBI accession Length (nt)
Human NM_006078.5 5642
Mouse NM_007583.2 2887
Rat NM_053351.2 1120
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Protein Isoforms

Species Uniprot ID Length (aa)
Human Q9Y698 323
Mouse O88602 323
Rat Q71RJ2 323

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

PTM
Position
Type
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Structure

The eight calcium channel c subunits share a predicted structure that includes four transmembrane domains with intracellular N- and C- termini (Fig. 1 in Chen [1310]). They are members of a large protein superfamily (pfam00822, a subset of the tetraspanin supergroup) that also includes claudins, proteins that are important components of tight junctions in epithelia. The c subunits share with the claudins a conserved GLW motif of unknown significance in the first extracellular loop. (Chen [1310])

The four c subunits identified as regulators of AMPA receptor function (c2, c3, c4, and c8; the TARPs) are widely expressed in the brain and share highly conserved sequences that are quite distinct from c1 and c6 (Arikkath [1324], Black [478]). Notably, the cytoplasmic C-terminal regions of the TARPs contain a number of regulatory sites including a PDZ-binding motif. This PDZ-binding motif (TTPV) is critical for targeting AMPA receptors to the synapse. (Chen [1310])

Cavγ2 predicted AlphaFold size

Species Area (Å2) Reference
Human 3752.13 source
Mouse 4348.65 source
Rat 4199.90 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Function

c2, c3, and c4 are reported to hyperpolarize the voltage-dependence of inactivation of Cav2.1 (HVA) current by 3–7 mV (Klugbauer [1328], Letts [1329], Rousset [1330]). However, the direction of this shift is apparently altered when a b subunit is co-expressed (Rousset [1330]). Two studies have reported small (3–5 mV) shifts in the voltage- dependence of activation by c2 but in different directions (Klugbauer [1328], Rousset [1330]). The only reported effect of c2, c3, and c4 on Cav3.3 (LVA) current is that c2 slows the deactivation rate of Cav3.3 channel (Green [240]). Unlike the results with c1 and c6, significant decreases in current amplitude were not rou- tinely found with any of the TARPs, although modulation of Cav2 current amplitude has been reported (Kang [239]). Currently, there is no evidence supporting an effect of these subunits on calcium currents in native cells. Specifically, there are no observable changes in calcium currents recorded from cerebellar granule neurons in the stargazer mouse in which the c2 gene is mutated (Chen [1331]).

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Interaction

In addition to the critical PDZ-binding motif, the C-terminal regions of the four gamma (c) subunits known as the TARPs (c2, c3, c4, c8) also contain regulatory sites that control AMPA receptor targeting. For instance, the second threonine in the PDZ-binding motif (TTPV) of c2 (=cacng2) is a consensus site for phosphorylation by PKA, PKC, PKG, and CaMKII suggesting that phosphorylation may regulate the interaction between c2 and the AMPA receptor. Indeed, two groups have independently found that phosphorylation by PKA interfered with the binding between c2 and PSD-95 (Chetkovich [1325], Choi [1326]). Consequently, reduced synaptic targeting of c2 prevents its interaction with the AMPA receptor, resulting in weakened synaptic efficiency (Choi [1326]).

References

478

Black JL The voltage-gated calcium channel gamma subunits: a review of the literature.
J. Bioenerg. Biomembr., 2003 Dec , 35 (649-60).

1310

Chen RS et al. Calcium channel gamma subunits: a functionally diverse protein family.
Cell Biochem. Biophys., 2007 , 47 (178-86).

1323

Nissenbaum J et al. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2.
Genome Res., 2010 Sep , 20 (1180-90).

1324

Arikkath J et al. Auxiliary subunits: essential components of the voltage-gated calcium channel complex.
Curr. Opin. Neurobiol., 2003 Jun , 13 (298-307).

1326

Choi J et al. Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95.
J. Biol. Chem., 2002 Apr 5 , 277 (12359-63).

1328

Klugbauer N et al. A family of gamma-like calcium channel subunits.
FEBS Lett., 2000 Mar 24 , 470 (189-97).

1329

Letts VA et al. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit.
Nat. Genet., 1998 Aug , 19 (340-7).

1331

Chen L et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
Nature, 2000 Dec 21-28 , 408 (936-43).

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Credits

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/93/ , accessed on 2024 Nov 21


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