8.A.92.  The G-Protein αβγ Complex (GPC) Family 

G-proteins, including either the α-subunit (Galpha) or the βγ-subunit complex (Gbetagamma), regulate a variety of channels (TC class 1) and transport systems (carriers and primary active transporters ;TC classes 2 and 3, respectively). For example, ACh enhances calcium channel, Cav1.2b currents via muscarinic M2 receptors that couple sequentially to Gbetagamma, PI3K, a novel PKC, and c-Src (Callaghan et al. 2004), and the calcium channel, Cav2 is regulated by G-proteins (Currie 2010; Zamponi and Currie 2013). Also, The G protein-coupled inwardly rectifying K+ channel, GIRK1/GIRK4, can be activated by receptors coupled to the Galpha(i) subunit (Hill and Peralta 2001). Moreover, neuronal G protein-coupled inwardly-rectifying potassium channels (GIRKs, Kir3.x) can be activated or inhibited by distinct classes of receptors (Galphai/o and Galphaq/11-coupled, respectively), providing dynamic regulation of neuronal excitability. Lei et al. 2003 used a mammalian heterologous expression system to address mechanisms of GIRK channel regulation by Galpha and Gbetagamma subunits. Like beta1- and beta2-containing Gbetagamma dimers, GIRK channels are also activated by G protein betagamma dimers containing beta3 and beta4 subunits, but are inhibited by beta5-containing Gbetagamma dimers and/or by Galpha proteins of the Galphaq/11 family. The properties of Gbeta5-mediated inhibition suggest that beta5-containing Gbetagamma dimers act as competitive antagonists of other activating Gbetagamma pairs on GIRK channels (Lei et al. 2003). G-protein-coupled receptors control Ca2+ entry and Ca2+-dependent events such as neurotransmitter and hormone release (McDavid and Currie 2006). Finally, Gαi2 activates the TRPC4 channel by direct binding, which then induces Ca2+ entry (Myeong et al. 2015), and the G protein betagamma subunit complex modulates ionotropic glycine receptors, GlyRs (Yevenes et al. 2006).

Beta3 regulates the formation of transport carriers at the trans golgi nextwork (TGN), and fission of transport carriers at the TGN is dependent on PLCbeta3, which is necessary to activate PKCeta and PKD in that Golgi compartment, via DAG production (Díaz Añel 2007). 

Two Gbetagamma dimers of the Arabidopsis thaliana heterotrimeric G protein complex are differentially localized to the central and cortical tissues of the Arabidopsis roots. A null mutation in either the single beta (AGB1) or the two gamma (AGG1 and AGG2) subunits alters auxin transport (Mudgil et al. 2009).



Callaghan, B., S.D. Koh, and K.D. Keef. (2004). Muscarinic M2 receptor stimulation of Cav1.2b requires phosphatidylinositol 3-kinase, protein kinase C, and c-Src. Circ Res 94: 626-633.

Currie, K.P. (2010). G protein modulation of CaV2 voltage-gated calcium channels. Channels (Austin) 4: 497-509.

Díaz Añel, A.M. (2007). Phospholipase C beta3 is a key component in the Gbetagamma/PKCeta/PKD-mediated regulation of trans-Golgi network to plasma membrane transport. Biochem. J. 406: 157-165.

Guardia, C.M., A. Jain, R. Mattera, A. Friefeld, Y. Li, and J.S. Bonifacino. (2021). RUSC2 and WDR47 oppositely regulate kinesin-1-dependent distribution of ATG9A to the cell periphery. Mol. Biol. Cell 32: ar25.

Harashima, T. and J. Heitman. (2005). Galpha subunit Gpa2 recruits kelch repeat subunits that inhibit receptor-G protein coupling during cAMP-induced dimorphic transitions in Saccharomyces cerevisiae. Mol. Biol. Cell 16: 4557-4571.

Hilger, D., K.K. Kumar, H. Hu, M.F. Pedersen, E.S. O''Brien, L. Giehm, C. Jennings, G. Eskici, A. Inoue, M. Lerch, J.M. Mathiesen, G. Skiniotis, and B.K. Kobilka. (2020). Structural insights into differences in G protein activation by family A and family B GPCRs. Science 369:.

Hill, J.J. and E.G. Peralta. (2001). Inhibition of a Gi-activated potassium channel (GIRK1/4) by the Gq-coupled m1 muscarinic acetylcholine receptor. J. Biol. Chem. 276: 5505-5510.

Hu, Y., M.A. Benedict, L. Ding, and G. Núñez. (1999). Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO. J. 18: 3586-3595.

Ikebuchi, Y., T. Takada, K. Ito, T. Yoshikado, N. Anzai, Y. Kanai, and H. Suzuki. (2009). Receptor for activated C-kinase 1 regulates the cellular localization and function of ABCB4. Hepatol Res 39: 1091-1107.

Jaskolka, M.C., S.R. Winkley, and P.M. Kane. (2021). RAVE and Rabconnectin-3 Complexes as Signal Dependent Regulators of Organelle Acidification. Front Cell Dev Biol 9: 698190.

Key, J., A.K. Mueller, S. Gispert, L. Matschke, I. Wittig, O. Corti, C. Münch, N. Decher, and G. Auburger. (2019). Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons. Neurobiol Dis 127: 114-130.

Lei, Q., M.B. Jones, E.M. Talley, J.C. Garrison, and D.A. Bayliss. (2003). Molecular mechanisms mediating inhibition of G protein-coupled inwardly-rectifying K+ channels. Mol. Cells 15: 1-9.

Li, S., Y. Li, B.R. Rushing, S.E. Harris, S.L. McRitchie, D. Dominguez, S.J. Sumner, and H.G. Dohlman. (2022). Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast. Biomolecules 12:.

McDavid, S. and K.P. Currie. (2006). G-proteins modulate cumulative inactivation of N-type (Cav2.2) calcium channels. J. Neurosci. 26: 13373-13383.

Mudgil, Y., J.F. Uhrig, J. Zhou, B. Temple, K. Jiang, and A.M. Jones. (2009). Arabidopsis N-MYC DOWNREGULATED-LIKE1, a positive regulator of auxin transport in a G protein-mediated pathway. Plant Cell 21: 3591-3609.

Myeong, J., M. Kwak, J.P. Jeon, C. Hong, J.H. Jeon, and I. So. (2015). Close spatio-association of the transient receptor potential canonical 4 (TRPC4) channel with Gαi in TRPC4 activation process. Am. J. Physiol. Cell Physiol. 308: C879-889.

Ogawa, T., K. Shiga, S. Hashimoto, T. Kobayashi, A. Horii, and T. Furukawa. (2003). APAF-1-ALT, a novel alternative splicing form of APAF-1, potentially causes impeded ability of undergoing DNA damage-induced apoptosis in the LNCaP human prostate cancer cell line. Biochem. Biophys. Res. Commun. 306: 537-543.

Versele, M., J.H. de Winde, and J.M. Thevelein. (1999). A novel regulator of G protein signalling in yeast, Rgs2, downregulates glucose-activation of the cAMP pathway through direct inhibition of Gpa2. EMBO. J. 18: 5577-5591.

Wang, W., Y. Li, L. Wang, X. Chen, T. Lan, C. Wang, S. Chen, and S. Yu. (2024). FBXL20 promotes synaptic impairment in depression disorder via degrading vesicle-associated proteins. J Affect Disord 349: 132-144. [Epub: Ahead of Print]

Yevenes, G.E., G. Moraga-Cid, L. Guzmán, S. Haeger, L. Oliveira, J. Olate, G. Schmalzing, and L.G. Aguayo. (2006). Molecular determinants for G protein betagamma modulation of ionotropic glycine receptors. J. Biol. Chem. 281: 39300-39307.

Zamponi, G.W. and K.P. Currie. (2013). Regulation of Ca(V)2 calcium channels by G protein coupled receptors. Biochim. Biophys. Acta. 1828: 1629-1643.

Zheng, H., L. Ma, R. Gui, X. Lin, X. Ke, X. Jian, C. Ye, and Q. Chen. (2022). G Protein Subunit β1 Facilitates Influenza A Virus Replication by Promoting the Nuclear Import of PB2. J. Virol. 96: e0049422.


TC#NameOrganismal TypeExample

G-protein α, β, and γ subunits.  Guanine nucleotide-binding proteins (G proteins) are modulators or transducers in various transmembrane signaling systems including transporters (channels and carriers) (see Family description). G protein subunit beta1 plays a role in regulating transmembrane signal transduction, but it also facilitates influenza A virus replication by promoting the nuclear import of the RNA polymerase subunit, PB2 (Zheng et al. 2022). 



G-protein α, β, and γ subunits of Homo sapiens


SEC12 of 417 aas and 3 TMSs, one N-terminal and two near the C-terminus.

SEC12 of Homo sapiens


Apoptotic protease-activating factor 1, APAF-1, of 1248 aas.  Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis (Hu et al. 1999, Ogawa et al. 2003). Physiological concentrations of calcium ions negatively affect the assembly of apoptosome by inhibiting nucleotide exchange in the monomeric form.

APAF-1 of Homo sapiens


Katanin p80 WD40 hydrophilic repeat-containing subunit B1 homologue of 823 aas and 2 - 3 N-terminal TMSs plus 2-3 possible C-terminal TMSs.  May participate in a complex which severs microtubules in an ATP-dependent manner. Microtubule severing may promote rapid reorganization of cellular microtubule arrays. This protein has at least 4 repeats of about 42 aas (WD40).  The protein is an AAA ATPase which targets centrosomes (Hartman et al. 1998). p80 katanin is targeted to spindle poles through a combination of direct microtubule binding by the p60 subunit and through interactions between the WD40 domain and an unknown protein (McNally et al. 2000).

Katanin of Arabidopsis thaliana (Mouse-ear cress)


Dmx-like protein 2, DMXL2 or Rabconnectin-3, of 3036 aas. It is a component of intercellular desmosome junctions and plays a role in stratified epithelial integrity and cell-cell adhesion by promoting desmosome assembly. It also functions as an effector in the TP53-dependent apoptotic pathway. DMXL2, a gene encoding the rabconnectin-3α vesicular protein, is present in human subjects with mental retardation and neuroendocrine impairment of reproduction (Wahab et al. 2017). Rabconnectin-3 complexes of higher eukaryotes regulate acidification of organelles such as lysosomes and endosomes by facilitating V-ATPase assembly (Jaskolka et al. 2021).


DMXL2 of Homo sapiens


Cell division cycle protein 20 homolog of 499 aas and 0 TMSs. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons (Yang et al. 2009). CDC20 is differentially expressed in glioma (Xu et al. 2020).

CDC20 of Homo sapiens


Heteromeric 7 TMS glucose receptors coupled with two large G-proteins, Ras1 and Ras2 of 309 and 3322 aas, respectively, both with 1 N-terminal TMS. One subunit is called the guanine nucleotide-binding protein, alpha-2 subunit, Gpa2 of 449 aas and 6 - 8 TMSs, and the other is called the guanine nucleotide binding protein, GPR1, of 961 aas and 6 - 8 TMSs. They comprise a hetero-tri- or tetra-meric guanine nucleotide-binding protein (G protein) complex, involved in glucose-induced cAMP signaling. These two cognate transmembrane G-protein receptors bind to each other, which sense extracellular carbon sources, and activate cAMP-PKA signaling to govern diploid pseudohyphal differentiation and haploid invasive growth. The G protein beta-mimic proteins, GPB1 (Q08886) and GPB2 (P39717) inhibit GPA2-GPR1 coupling, probably to reduce signaling in the absence of glucose (Versele et al. 1999; Harashima and Heitman 2005). The S. cerevisiae Ras proteins, amoung other things, modulate the activity of the adenylate cyclase catalytic subunit and therefore alter the biosynthesis of cyclic-AMP. A multi-omics analysis of multiple glucose-sensing receptor systems in yeast has appeared (Li et al. 2022).


Gpr1/Gpa2 with Ras1 and/or Ras2 of Saccharomyces cerevisiae


WD repeat-containing protein 47, WDR47, of 919 aas and 0 TMSs. RUSC2 and WDR47 oppositely regulate kinesin-1-dependent distribution of ATG9A to the cell periphery (Guardia et al. 2021).

WDR47 of Homo sapiens


FBXL20 protein of 436 aas and 1 N-terminal TMS.  An N-terminal region is similar in sequence to that of TC# 8.A.92.1.6.  It promotes synaptic impairment in depression disorder by degrading vesicle-associated proteins (Wang et al. 2024).

FBXL20 of Homo sapiens


G-protein complex with subunits α, β, γ1 and γ2. 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 (Mudgil et al. 2009).

G-protein heterotrimeric complex of Arabidopsis thaliana (Mouse-ear cress)


G-protein subunits α, β1, β2 and γ.   The exchange of GDP for GTP on the G protein alpha subunit alters its interaction with the G protein beta subunit, leading to dissociation of the G protein beta-gamma dime. The dissociated subunits activate downstream effectors.

G-protein subunits α, β, and γ of Saccharomyces cerevisiae (Baker's yeast)


Receptor of activated protein C kinase 1 of 317 aas and 0 TMSs. Scaffolding protein involved in the recruitment, assembly and/or regulation of a variety of signaling molecules. It is nvolved in PKC-dependent translocation of ADAM12 to the cell membrane and promotes ubiquitination and proteasome-mediated degradation of proteins such as CLEC1B and HIF1A. It is required for VANGL2 membrane localization, inhibits Wnt signaling, and regulates cellular polarization and oriented cell division during gastrulation. It regulates internalization of the muscarinic receptor CHRM2 and promotes apoptosis by increasing oligomerization of BAX while disrupting the interaction of BAX with the anti-apoptotic factor BCL2L. It inhibits TRPM6 channel activity and regulates cell surface expression of some GPCRs. Involved in the transport of ABCB4 from the Golgi to the apical bile canalicular membrane (Ikebuchi et al. 2009).

Receptor of Homo sapiens


Guanine nucleotide-binding protein, subunit alpha-11, GNA11 of 359 aas.  It is a modulator or transducers of various transmembrane signaling systems. It may alter the firing of noradrenergic neurons (Key et al. 2019).


GNA11 of Homo sapiens


Uncharacterized protein of 842 aas and 1 N-terminal TMS.

UP of Botryotinia calthae


Beta2-adrenaline receptor, β2AR or GNB2, of 340 aas (Hilger et al. 2020). It is 91% identical to GNB1 (TC# 8.A.92.1.1). This protein seems to consist of several internal WD40 repeats of about 45 aas.

GNB2 of Homo sapiens


NACHT domain-containing protein of 1406 aas and 1 central TMS.

NACHT domain protein of Chloroflexi bacterium


SEC12-like protein 1 isoform X1 of 388 aas and one C-terminal TM

SEC12 of Camellia sinensis


TC#NameOrganismal TypeExample