Channelpedia

Cavγ4

Description: calcium channel, voltage-dependent, gamma subunit 4
Gene: cacng4
Alias: cacng4

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Introduction

The protein encoded by CACNG4 (also known as MGC11138; MGC24983) is a type I transmembrane AMPA receptor regulatory protein (TARP), also known as gamma4 (c4) 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 and is located in a cluster with two family members, a type II TARP and another calcium channel gamma subunit.

http://www.ncbi.nlm.nih.gov/gene/27092


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Gene

Phylogenetic analysis suggests that all c subunits evolved from a single ancestral gene through tandem repeat and chromosome duplication (Burgesse [1312], Chu [1311]). 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) (Burgesse [1312], Chu [1311]). See also the phylogenetic tree, fig.2 in Black [478].

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]).

Species NCBI gene ID Chromosome Position
Human 27092 17 68691
Mouse 54377 11 62349
Rat 140725 10 59501

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Transcript

Species NCBI accession Length (nt)
Human NM_014405.4 3583
Mouse NM_019431.4 3649
Rat NM_080692.1 984

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Protein Isoforms

Species Uniprot ID Length (aa)
Human Q9UBN1 327
Mouse Q9JJV4 327
Rat Q8VHW9 327

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 cytoplasmic C-terminal regions of the TARPs (to which cacng4 = gamma4 = c4 belongs) 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]

Cavγ4 predicted AlphaFold size

Species Area (Å2) Reference
Human 3163.62 source
Mouse 3112.85 source
Rat 3475.90 source

Methodology for AlphaFold size prediction and disclaimer are available here


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Expression and Distribution

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]).

γ 4 mRNA was highly expressed in caudate putamen, olfactory bulb, habenulae and less so in cerebellum and thalamus. γ 2 and γ 4 expression in cerebellum came predominantly from Purkinje cells. (Black [478])

γ 4 was expressed broadly in brain with very strong expression in fetal brain and some increased expression in caudate nucleus, putamen, and thalamus. There was substantial expression in prostate and lung and less expression in testes, stomach, pancreas, small intestine, placenta, and uterus. Because γ 4 was highly expressed in fetal brain, it is hypothesized to have a potential role during development. This hypothesis is supported by Kious et al. (2002) [1334] who found γ 4 expression in the chick cranial neural plate and in the cranial and dorsal root ganglia. Timing of expression correlates precisely with the onset of neuronal differentiation. γ 4 expression is also observed in the myotome and a subpopulation of differentiating myoblasts in the limb bud. In the distal cranial ganglia, γ 4 expression was detected in cells destined to become neurons and neural crest cells. The authors hypothesize that γ 4’s subtle effects on VGCC calcium transients effects neuronal differentiation. (Black [478])


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Interaction

The most distinct features of the TARPs are the terminal PDZ-binding motifs overlapped with PKA phosphorylation sites. The terminal TTPV motif is known to interact with PSD-95 in the postsynaptic density and the binding is regulated by the PKA motif immediately preceding the PDZ-binding motif (Chetkovich [1325], Choi [1326]). In addition to the critical PDZ-binding motif, the C-terminal regions of the four c subunits known as the TARPs (c2, c3, c4, c8) also contain regulatory sites that control AMPA receptor targeting. (Chen [1310])


References


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Credits

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/95/ , accessed on 2024 Dec 02



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