HGNC Approved Gene Symbol: RGS12
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:3,285,891-3,439,913 (from NCBI)
Members of the 'regulator of G protein signaling' (RGS) gene family encode proteins that act as GTPase-activating proteins. They contain a block of approximately 120 amino acids that spans 3 conserved motifs termed GH1, GH2, and GH3. See 602189 for more background information.
To identify additional Rgs genes expressed in rat brain, Snow et al. (1997) performed PCR on rat glioma cell cDNA using primers based on the GH1 and GH3 domains. They identified 2 novel rat cDNAs, Rgs12 and Rgs14 (602513). The Rgs12 cDNA encodes a predicted 1,387-amino acid protein containing an N-terminal domain that is highly homologous to Rho-interacting mouse rhophilin (601031), an RGS domain, and a C-terminal coiled-coil domain. Northern blotting showed that Rgs12 is expressed as multiple transcripts, with high levels in brain and lung and lower levels in testis, heart, and spleen.
By database searching, Snow et al. (1997) identified the human RGS12 gene sequence within several cosmids that map to 4p16.3. The predicted RGS12 gene encodes a 1,376-amino acid protein that is 85% identical to rat Rgs12.
Snow et al. (1998) identified 4 alternatively spliced forms of human RGS12 mRNA. They demonstrated that the N terminus of rat and human RGS12 has a PDZ domain (named for PSD-95/Dlg/ZO-1). They showed in vitro binding of this domain to the C terminus of G protein-coupled receptors.
Gamma-aminobutyric acid beta receptors (see GABRB1; 137190) couple to G0 to inhibit N-type calcium channels in embryonic chick dorsal root ganglion neurons. The voltage-independent inhibition, mediated by means of a tyrosine-kinase pathway, is transient and lasts up to 100 seconds. Inhibition of endogenous RGS12 selectively alters the time course of voltage-independent inhibition. The RGS12 protein contains a PTB domain (De Vries and Farquhar, 1999) in addition to the RGS and PDZ domains. Fusion proteins containing the PTB domain of RGS12 alter the rate of termination of the GABRB signal, whereas those containing the PDZ or RGS domains have no observable effects. Schiff et al. (2000) used primary dorsal root ganglion neurons in culture to demonstrate an endogenous agonist-induced tyrosine-kinase-dependent complex of RGS12 and the calcium channel. The results indicated that RGS12 is a multifunctional protein capable of direct interactions through its PTB domain with the tyrosine-phosphorylated calcium channel. Recruitment of RGS proteins to G protein effectors may represent an additional mechanism for signal termination in G protein-coupled pathways.
Snow et al. (1997) stated that the human RGS12 gene contains at least 16 exons. Sierra et al. (2002) determined that the RGS12 gene contains 16 exons and spans 123 kb.
By genomic sequence analysis, Sierra et al. (2002) mapped the RGS12 gene to chromosome 4p16.2. They mapped the mouse Rgs12 gene to chromosome 5 by interspecific backcross mapping.
De Vries, L., Farquhar, M. G. RGS proteins: more than just GAPs for heterotrimeric G proteins. Trends Cell Biol. 9: 138-144, 1999. [PubMed: 10203790] [Full Text: https://doi.org/10.1016/s0962-8924(99)01515-9]
Schiff, M. L., Siderovski, D. P., Jordan, J. D., Brothers, G., Snow, B., De Vries, L., Ortiz, D. F., Diverse-Pierluissi, M. Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature 408: 723-727, 2000. [PubMed: 11130074] [Full Text: https://doi.org/10.1038/35047093]
Sierra, D. A., Gilbert, D. J., Householder, D., Grishin, N. V., Yu, K., Ukidwe, P., Barker, S. A., He, W., Wensel, T. G., Otero, G., Brown, G., Copeland, N. G., Jenkins, N. A., Wilkie, T. M. Evolution of the regulators of G-protein signaling multigene family in mouse and human. Genomics 79: 177-185, 2002. [PubMed: 11829488] [Full Text: https://doi.org/10.1006/geno.2002.6693]
Snow, B. E., Antonio, L., Suggs, S., Gutstein, H. B., Siderovski, D. P. Molecular cloning and expression analysis of rat Rgs12 and Rgs14. Biochem. Biophys. Res. Commun. 233: 770-777, 1997. [PubMed: 9168931] [Full Text: https://doi.org/10.1006/bbrc.1997.6537]
Snow, B. E., Hall, R. A., Krumins, A. M., Brothers, G. M., Bouchard, D., Brothers, C. A., Chung, S., Mangion, J., Gilman, A. G., Lefkowitz, R. J., Siderovski, D. P. GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. J. Biol. Chem. 273: 17749-17755, 1998. [PubMed: 9651375] [Full Text: https://doi.org/10.1074/jbc.273.28.17749]