6dde

Structural highlights

Function

[GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.^{[1] [2]} [GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.^[3] [OPRM_MOUSE] Receptor for endogenous opioids such as beta-endorphin and endomorphin. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross-activate GRPR in response to morphine.^{[4] [5] [6] [7] [8] [9]}

See Also

• Opioid receptor
• Transducin 3D structures

References

1. ↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
2. ↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
3. ↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
4. ↑ George SR, Fan T, Xie Z, Tse R, Tam V, Varghese G, O'Dowd BF. Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem. 2000 Aug 25;275(34):26128-35. PMID:10842167 doi:http://dx.doi.org/10.1074/jbc.M000345200
5. ↑ Rios C, Gomes I, Devi LA. mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol. 2006 Jun;148(4):387-95. Epub 2006 May 8. PMID:16682964 doi:http://dx.doi.org/10.1038/sj.bjp.0706757
6. ↑ Milan-Lobo L, Whistler JL. Heteromerization of the mu- and delta-opioid receptors produces ligand-biased antagonism and alters mu-receptor trafficking. J Pharmacol Exp Ther. 2011 Jun;337(3):868-75. doi: 10.1124/jpet.111.179093. Epub , 2011 Mar 21. PMID:21422164 doi:http://dx.doi.org/10.1124/jpet.111.179093
7. ↑ Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature. 2012 Mar 21. doi: 10.1038/nature10954. PMID:22437502 doi:10.1038/nature10954
8. ↑ Kaufman DL, Keith DE Jr, Anton B, Tian J, Magendzo K, Newman D, Tran TH, Lee DS, Wen C, Xia YR, et al.. Characterization of the murine mu opioid receptor gene. J Biol Chem. 1995 Jun 30;270(26):15877-83. PMID:7797593
9. ↑ Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, Miner LL, Uhl GR. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1544-9. PMID:9037090
10. ↑ Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, Latorraca NR, Hilger D, Dawson R, Matile H, Schertler GFX, Granier S, Weis WI, Dror RO, Manglik A, Skiniotis G, Kobilka BK. Structure of the micro-opioid receptor-Gi protein complex. Nature. 2018 Jun 13. pii: 10.1038/s41586-018-0219-7. doi:, 10.1038/s41586-018-0219-7. PMID:29899455 doi:http://dx.doi.org/10.1038/s41586-018-0219-7