Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_171


Historical Background

Discovery of Ric-8 proteins: The Caenorhabditis elegans RIC-8 gene and a homologous mouse gene that was later termed Ric-8A (or a synembryn) were discovered by Miller and Rand using a genetic screen to obtain C. elegans mutants that were resistant to the inhibitor of cholinesterase, aldicarb (Miller et al. 1996). Aldicarb treatment of wild-type worms leads to neurotoxic accumulation of postsynaptic acetylcholine and subsequent death. Ric mutants lived in the presence of aldicarb because they contained gene defects that restored normal acetylcholine levels, primarily by decreasing neurotransmitter secretion or release. Through epistasis analyses, the gene complementing the ric-8 mutant allele was predicted to elicit action upstream of or parallel to the gene encoding G protein α q in a diacylglycerol-dependent synaptic-vesicle-priming pathway (Miller et al. 2000). Miller and Rand also first showed that centrosome (spindle pole) movements in the dividing C. elegans zygote were perturbed in ric-8 mutants, a phenotype shared by G protein αo(i) mutants (Miller and Rand 2000).

Ric-8 proteins were first linked physically to  G protein α subunits when two mammalian Ric-8 homologues were identified by the ability to bind Gαo and Gαs directly in yeast two-hybrid screens and in purified protein–protein binding and functional assays (Tall et al. 2003). The two homologues are the products of separate genes and were named mammalian Ric-8A and Ric-8B. Ric-8A binds Gαi, Gαq, and Gα12/13 class G protein α subunits, whereas Ric-8B binds the Gαs, Gαq, and Gα12/13 classes. Preliminary experiments demonstrating a preferred interaction of Ric-8A with the GDP-bound form of G protein α led to the hypothesis that Ric-8A might alter G protein catalysis by serving as an alternative guanine nucleotide dissociation inhibitor (GDI), or a non-receptor guanine nucleotide exchange factor (GEF). Purified Ric-8A stimulated intrinsic G protein α GDP release dramatically leading to accelerated, observed GTP(γS) binding kinetics (G protein activation) (Fig. 1). The mechanism of Ric-8A-stimulated guanine nucleotide exchange was elucidated. Ric-8A initially interacted with GDP-bound G alpha and stimulated rapid GDP release. In the absence of GTP, Ric-8A formed a stable nucleotide-free transition state complex with Gα. Addition of GTP and magnesium dissociated this complex to produce free Ric-8A and activated Gα-GTP. Currently, a biochemical characterization of Ric-8B has not been made. Ric-8B is predicted to be a Gαs and Gαq-class GEF based on its Gα binding preferences. Since these initial observations of Ric-8 function, the field has endeavored to understand how Ric-8 GEF activity regulates G protein function in cells. Many of the predicted Ric-8 physiological functions have been acquired from genetic studies in model organisms. These include functional interactions with varied G protein species to regulate neurotransmission, asymmetric cell division, olfaction, and G protein residence at the plasma membrane.
Ric-8, Fig. 1

Ric-8A is a Gα subunit GEF and accelerates the kinetics of (a) Gαq and (b) Gαi1 GTPγS binding. Purified Gα subunits (200 nM) were incubated in reactions containing radiolabeled GTPγS with (squares), or without (circles) purified Ric-8A (200 nM). At the indicated times, Gα and its bound nucleotide were trapped on nitrocellulose filters and the amount bound GTPγS was measured by scintillation counting. This research was originally published in the Journal of Biological Chemistry (4) © the American Society for Biochemistry and Molecular Biology

C. elegans RIC-8 and Gαq/Gαs/Gαo modulate neurotransmission. The original function ascribed to the C. elegans RIC-8 gene was made by its identification in the ric mutant screen designed to isolate mutants of genes whose products positively regulated neurotransmission (Miller et al. 1996). Gαq is one other such gene. Various genetic and biochemical tests confirmed that ric-8 mutants acted epistatically (upstream) to other Gαq-pathway-dependent synaptic-vesicle-priming defects. Gαq gain of function alleles, diacylglycerol (DAG) kinase mutants (deregulates DAG by phosphorylation), or application of phorbol esters (DAG analogs) all suppressed the ric-8 mutant neurotransmission defect (Miller et al. 2000). These and other collective observations indicated that the RIC-8 protein likely acted upstream of Gαq to promote neurotransmission through phospholipase Cβ-dependent DAG production and subsequent UNC13 stimulation (see Fig. 2). UNC13 is a DAG binding protein/sensor that interacts with the membrane in a DAG-dependent manner. UNC13 also interacts with syntaxin proteins and may regulate SNARE-dependent vesicle fusion.
Ric-8, Fig. 2

Proposed pathways depicting C. elegans RIC-8 control of Gαq- and Gαs-dependent neurotransmission (Arrows: activation, Bars: inhibition). Genetic experiments showed that the requirement of the RIC-8 gene for neurotransmission was manifested before the action of the Gαq and Gαs genes. G proteins αq and αs provide divergent inputs to regulate neurotransmitter release through the activation of phospholipase Cβ and adenylyl cyclase, respectively. These two pathways converge to modulate UNC13 function/localization and regulation of synaptic vesicle priming. G protein αo provides an inhibitory input into the pathway, perhaps through diacylglycerol kinase that is regulated by a serotonin responsive GPCR. Gαo regulation was not necessarily thought to involve RIC-8 (5–7)

Ric-8 was later shown to be epistatic to Gαs through genetic suppression experiments. Gain of function mutants in Gαs,  adenylyl cyclase, or protein kinase A individually suppressed the ric-8 paralysis defect (Reynolds et al. 2005; Schade et al. 2005). This showed that C. elegans RIC-8 gene action intersected with a second G protein, Gαs, to provide a cAMP second messenger input into the neurotransmitter release process. Collectively the C. elegans RIC-8 gene acts upstream of at least Gαq and Gαs and may maintain both G protein signaling pathways in activated states. It is not understood precisely how RIC-8 acted upon these divergent G proteins. The proposed role was gathered from the observation that mammalian Ric-8A acted as a Gαq GEF and directly activated these G proteins in a manner apart from the action of G protein–coupled receptors (GPCRs).

Ric-8 and G protein αi control of (asymmetric) cell division: Asymmetric cell division (ACD) is a process by which stem cells or progenitor cells divide such that the two daughter cells adopt unique characteristics and cell fate determinants during division (intrinsic ACD), or acquire these characteristics after division by influence of the surrounding tissue/niche (extrinsic ACD). ACD allows one daughter cell to retain stem/progenitor potential and the other to adopt a committed fate. Ric-8 and members of the G protein αi class of G proteins have an essential role in directing intrinsic asymmetric-, and perhaps normal-cell division. Gαi regulation in this context is thought to be GPCR-independent, as Gαi-family members reside not only on the plasma membrane, but on intracellular mitotic structures including spindle poles (centrosomes), spindle microtubules, and the cytokinesis midbody (Blumer et al. 2006).

The protein machinery that works with Gαi to control cell division is conserved and consists of components discovered in worms, flies, and mammals. Gαi, Ric-8(A), and orthologous GoLoco- or GPR-domain containing proteins, GPR1/2, PINS, or LGN/AGS3 in mammals are required for asymmetric cell division (ACD) of multiple cell types, including human adult progenitor cells. These and other conserved proteins in the pathway, including NuMA/Lin5/MUDs receive signals from cell polarity determinants to differentially regulate the strength of pulling forces on the two sets of aster microtubules during mitosis (for review and a comprehensive account of primary references, see Siderovski and Willard (2005), Siller and Doe (2009), Wilkie and Kinch (2005), and Yu et al. (2006)). This force differential pulls the entire mitotic spindle and metaphase plate as a unit toward one side of the cell. The asymmetric location of the metaphase plate marks the position of the cleavage plane for cytokinesis. Figure 3 depicts in cartoon format, the original observations demonstrating that the Ric-8, Gαi/o, and GPR1/2 genes were required for C. elegans zygote ACD. When these genes were mutated individually, zygotic cell division proceeded symmetrically, leading to developmental catastrophe and death at gastrulation.
Ric-8, Fig. 3

C. elegans zygote asymmetric cell division is perturbed in ric-8, gαo, or gpr1/2 mutants. Zygote polarity is determined by the site of sperm entry and designates the posterior (P), and anterior (A) sides of the zygote. During prophase the mitotic spindle (black microtubule bundles) rotates 90° (not depicted) to orient the spindle poles (red color) along the anterior and posterior axis of the zygote. Spindle rotation is an aster microtubule (brown color)-dependent process and is slowed in ric-8, gαo, or gpr1/2 mutants. Chromosomes (blue color) are shown aligned at the metaphase plate with intact mitotic spindles. The distance between spindle poles is reduced in ric-8, gαo, or gpr1/2 mutants. During meta/anaphase, the posterior spindle pole flattens and adopts a violent up and down rocking motion in relation to the A-P axis (green arrow) as it and the entire mitotic spindle is pulled toward the posterior side of the zygote by forces generated from the posterior aster microtubules. Overall aster microtubule force and the force differential between the anterior and posterior aster microtubules are considerably weaker in ric-8, gαo, or gpr1/2 mutants. The mutants exhibit a very weak rocking motion of the posterior spindle pole and reduced movement of either spindle pole toward the cell cortex. As chromosome segregation occurs, the cytokinetic cleavage plane appears asymmetrically in wild-type zygotes, closer to the posterior side. Ric-8, gαo, and gpr1/2 mutants lack asymmetrically oriented spindles and subsequently divide symmetrically

The majority of the genetic and cell biological work delineating the influence of this nontraditional G protein pathway on mitotic spindle dynamics has been learned from ACD model systems including the C. elegans zygote, Drosophila neuroblast, and sensory organ precursor cell. It is clear that the network also operates in mammals to direct both symmetric and ACD because homologous and orthologous components of the pathway influence keratinocyte (skin) progenitor cell ACD (LGN, NuMA), neural precursor development (LGN, AGS3, G protein subunits) (for review of primary literature see Siller and Doe (2009)), and division of COS and HeLa cells (Gαi, AGS3) (Blumer et al. 2006; Cho and Kehrl 2007). Recently, Ric-8A and Gαi were shown to recruit LGN, NuMA, and the dynein microtubule motor to the plasma membrane of mitotic HeLa cells. Perturbation of Ric-8A expression, or its interaction with Gαi resulted in defective orientation of the HeLa mitotic spindle to the substratum and aberrant cell division (Woodard et al. 2010).

A biochemical demonstration of Ric-8A, Gαi, and GoLoco protein concerted function accounts for how Ric-8 GEF activity could supplant the lack of apparent GPCR-mediated G protein activation in ACD and provides one cellular context for the GoLoco component as an atypical guanine nucleotide dissociation inhibitor (GDI). In conditions where traditional GPCR signaling is turned off, Gβγ subunits serve as a Gα protein GDI and prevent GDP release. During nontraditional G protein signaling in mitosis and ACD, LGN (GoLoco) binds plasma membrane-bound Gαi-GDP subunits as a GDI. The nuclear mitotic apparatus protein (NuMA) is recruited in allosteric fashion to a binding site on LGN that becomes available when LGN is bound to Gαi (Du and Macara 2004). NuMA is not active in this complex with respect to its incapacity to participate in direct interactions with microtubules (Du et al. 2002). However, complexed NuMA may interact with the dynein microtubule motor complex (Siller and Doe 2009). Ric-8A dissociated a purified Gαi/GoLoco/NuMA complex by removing Gαi-GDP from LGN or AGS3 (GoLoco) through stimulation of nucleotide exchange and production of free Gαi-GTP (Tall and Gilman 2005; Thomas et al. 2008). Once Gαi was dissociated from LGN, the ability of NuMA to bind GoLoco domains was decreased and NuMA was released. Whether the intact GoLoco protein complex or any of the released species (NuMA, GoLoco ortholog, and/or Gαi-GTP) regulate aster microtubule pulling forces to direct spindle asymmetry is not completely clear and is an area of considerable interest. It is unlikely that a static, plasma membrane–bound Gα-GDP:GoLoco complex is the sole form of the G protein responsible for force generation, as rounds of nontraditional G protein guanine nucleotide consumption seem to be required (Wilkie and Kinch 2005). Gαi-GTP is inactivated by RGS GTPase-activating-proteins, which presumably resets the system for another cycle of Ric-8-mediated activation (Hess et al. 2004). Important unresolved questions remain. Does Ric-8(A) actually perform this function in cells and dissociate Gαi/GoLoco/NuMA complexes in the context of aster microtubule force regulation? What is the precise ordering of molecular events that occur downstream of Ric-8A, the intact GoLoco complex, or the dissociated Gαi-GTP, GoLoco, and/or NuMA species that directly signal to the dynein motor complex force generator (Fig. 4)?
Ric-8, Fig. 4

Biochemical model comparing traditional GPCR-mediated activation of Gαβγ trimers and alternative Ric-8(A) activation of Gαi/GoLoco/NuMA complexes. In the traditional G protein signaling paradigm, inactive G protein trimers are bound to GDP. Gβγ serves as a GDI and prevents Gα subunit GDP release in the absence of GPCR activating ligand (●). Gβγ is also obligate for ligand-receptor complex stimulation of G protein GTP for GDP nucleotide exchange of the Gα subunit. Activated Gα-GTP and Gβγ transduce signals to downstream effector enzymes. In the proposed alternative Gα signaling model that regulates aster microtubule force generation during ACD, Gα-GDP is bound to the alternative GDI GoLoco. A mammalian GoLoco ortholog, LGN, contains four carboxyl-terminal GoLoco domains, and an amino-terminal tetratricopeptide repeat region that binds NuMA. Ric-8A binds Gαi-GDP, and in the process dissociates GDP from Gαi, and Gαi processively from GoLoco domains. GTP then rapidly binds the Ric-8A:Gα nucleotide-free complex producing free Ric-8A and Gα-GTP. As a consequence of Gα:GoLoco dissociation, NuMA is released from LGN and could be available to participate in enhanced interactions with microtubules or microtubule motors. Elucidation of the complete repertoire of molecules, or direct events that result in aster microtubule force generation is not entirely clear (10). Evidence in favor of G protein α i catalytic cycle involvement in this process comes from the finding that mutants of C. elegans RGS7 (an activator of G protein GTP hydrolysis) have many opposed phenotypes to ric-8, gαo, and gpr1/2 mutants during ACD (19)

Ric-8B and Gαolf regulation of olfaction: The second mammalian Ric-8 homologue was named Ric-8B after it was discovered in yeast two-hybrid screens intended to uncover Gαs-interacting proteins (Tall et al. 2003; Klattenhoff et al. 2003). Mammalian Ric-8/synembryn was renamed Ric-8A at this time. Ric-8A and Ric-8B share ∼40% overall amino acid identity. The amino-terminal ∼400 amino acids are more divergent (34% identity) and have been predicted to be highly α-helical in content and consist of weakly scoring Armadillo repeats (Wilkie and Kinch 2005). Ric-8A and Ric-8B share greater amino acid identity between the carboxyl-terminal 130–160 amino acids (∼56% identity). No obvious protein sub-domains are present in the predicted α-helical Ric-8 carboxyl-termini, but the region in Ric-8B is alternatively spliced.

Ric-8B binds all G protein alpha classes in vitro with the exception of the Gαi-class, and unlike Ric-8A, uniquely binds members of the Gαs-family (Tall et al. 2003; Klattenhoff et al. 2003). Evidence supports a role for Ric-8B in the regulation of Gαolf during olfaction (Von Dannecker et al. 2006). Gαolf is the olfactory/brain-specific Gαs homologue that activates adenylyl cyclase to stimulate olfactory nerve firing. Malnic and colleagues portrayed functional differences between two expressed Ric-8B splice variants (full length, FL and deleted exon 9, Δ9). Overexpression of Ric-8BFL, but not Ric-8BΔ9 enhanced Gαolf-dependent adenylyl cyclase activation (Von Dannecker et al. 2006). When Gαolf, Gβ, Gγ, odorant receptors, receptor co-factors, and Ric-8BFL, but not Ric-8BΔ9, were co-transfected into a heterologous system (HEK cells), functional odorant receptor coupling was achieved. Application of odorants activated Gαolf-dependent signaling (Von Dannecker et al. 2006; Zhuang and Matsunami 2007). The unresolved question raised from these studies is: Does Ric-8B promote odorant receptor signaling because it activates Gαolf/Gαs as a guanine nucleotide exchange factor, or because it facilitates functional Golf membrane expression in the heterologous system, thereby enhancing Golf coupling to odorant receptors? Overexpression of Ric-8BFL did increase the amount of overexpressed Golf in a crude membrane fraction (Kerr et al. 2008). It was later reported that the single copy of RIC-8 in Xenopus appeared to stimulate mammalian Gαs GTPγS binding, although the intrinsic rate of Gαs GTPγS binding reported in this study was negligible (Romo et al. 2008). A positive demonstration of mammalian Ric-8B protein function as a Gαs-class GEF has not been made as of yet (Nagai et al. 2010). Ric-8B is hypothesized to be a Gαs and Gαq-class GEF since it interacts with these subunits in vitro, and by analogy (and homology) to the described activities of Ric-8A. Ric-8A is a GEF for all Gα subunits that it can bind.

Ric-8 proteins support heterotrimeric G protein membrane expression: An alternative hypothesis of Ric-8 protein function was proposed from work performed on the sole copy of the Drosophila and C. elegans RIC-8 genes. Attenuation of Drosophila RIC-8 expression caused nearly complete and pleotropic loss of multiple Gα subunits and the major Gβ (and presumably Gγ) subunit from the plasma membrane (for review and primary literature references see Matsuzaki (2005)). Drosophila Gαi (Fig. 5), Gαo, and Gβ13F subunits were expressed in the cytosol or vesiculated compartments of Drosophila embryonic epithelial cells derived from larvae possessing both a maternal and zygotic P-element disruption of RIC-8. Overall steady-state expression levels of the mis-localized Gαi and Gβ were reduced in the absence of RIC-8. These findings were corroborated at the same time in C. elegans when cortical Gpa16 (a Gαi homologue) localization was attenuated in mitotic ric-8 mutant embryos (Afshar et al. 2005). More recently, RNAi-mediated reduction of mammalian Ric-8B resulted in reduced Gαs expression, and Ric-8B overexpression protected Gαs from ubiquitin-mediated degradation (Nagai et al. 2010). The provocative hypothesis arising from these findings is that the function of Ric-8 protein(s) may be to serve as key factors required for G protein subunit biosynthesis, or trafficking to, or retention at the plasma membrane. It is known that cytosolic G proteins are less stable than membrane-bound G proteins, so a shift of G proteins from the membrane to the cytosol in the absence of Ric-8 would be realized as a reduction in G protein steady-state expression levels. Aside from the finding that Ric-8B overexpression reduced levels of ubiquitinated Gαs, there is little understanding of the mechanism by which Ric-8-proteins mediate G protein membrane localization.
Ric-8, Fig. 5

Drosophila Gαi was mis-localized and not expressed on the plasma membrane when RIC-8 was P-element disrupted. Epithelial cells from (a) wild-type or (b) ric-8 mutant Drosophila embryos were stained with an anti-Gαi antibody (Green) and a DNA stain (Red) (Adapted by permission from Macmillan Publishers Ltd.: Nature Cell Biology, (28). 2005)


The hypothesis that Ric-8 proteins are required for efficient G protein membrane expression provides a potential explanation, in part, for the findings that Ric-8 proteins seem to exert affects upstream of divergent G protein signaling pathways (i.e., Gαq, synaptic transmission, Gαi, cell division, Gαolf olfaction, etc.). The one observation that cannot be explained intuitively by the idea that Ric-8 proteins are simply factors required for G protein expression is that Ric-8(A) is a mitotic spindle (pole) binding protein (Fig. 6 and Woodard et al. 2010; Hess et al. 2004). This result suggests that Ric-8A might participate as a non-receptor GEF to activate intracellular Gαi-class G proteins that are localized on mitotic structures, including the mitotic spindle.
Ric-8, Fig. 6

Ric-8A localizes proximally to the mitotic spindle poles. HeLa cells were transfected with YFP-Ric-8A (Yellow-green) and stained with DAPI (Blue) and by immunofluorescence with anti-α-tubulin monoclonal antibody (Sigma) and an anti-mouse Alexafluor-568 antibody. The tricolor images were captured using a Zeiss epifluorescence microscope with appropriate filters and subjected to nearest-neighbors deconvolution using Slidebook 4.0 software (unpublished observations)

There are multiple regulatory points where Ric-8 proteins could act to promote or stabilize G protein membrane expression. Ric-8 proteins might act during G protein biosynthesis in positive fashion to promote stable membrane expression, or they could exert a protective role upon mature membrane–bound G proteins as these G proteins cycle between the plasma membrane and endo-membranes. Biosynthetic (forward) trafficking of G proteins to the plasma membrane requires two basic events: (1) G protein heterotrimer assembly on the endoplasmic reticulum (ER) and/or Golgi and (2) covalent attachment of lipid moieties to Gα and Gγ subunits (Marrari et al. 2007). Chaperone proteins including phosducin-like protein-1 (PhLP) and DRIP78 bind nascent Gβ and Gγ proteins, respectively, prior to Gβγ dimer formation (Dupre et al. 2007; Lukov et al. 2005). No component is known that binds nascent Gα after its synthesis, and aids its assembly into G protein trimers. Ric-8 proteins could fulfill such a role. In the absence of Ric-8 expression, Gα subunits not assembled into trimers would not reach the plasma membrane and would be more susceptible to degradation.

Ric-8 proteins could also potentially function in a capacity to counteract G protein downregulation by promoting G protein subunit recycling to the membrane. Debate exists whether G protein subunits become “solubilized” from membranes or clustered into membrane micro-domains upon activation by hormone receptors. Ric-8A and Ric-8B reside predominantly in the cytosol. Perhaps Ric-8 proteins function to “scavenge” cytosolic Gα subunits to restore membrane association. Upon experimental perturbation of Ric-8 protein expression, Gα subunits might slowly “leach off” the membrane over time due to tonic GPCR stimulation. If the pace of Gα biosynthesis does not keep up, this would be realized as a reduction in steady-state G protein expression. G proteins also cycle between the plasma membrane and Golgi membranes, perhaps as a means to receive reversible palmitoylation at the Golgi. Heterotrimeric G protein retrograde movement to the Golgi occurs at a rate faster than that predicted of a vesicular-transport-mediated event (t1/2 < 1 min) (Chisari et al. 2007; Tsutsumi et al. 2009). As such, G proteins were predicted to transit diffusively through the cytosol to the Golgi. It is not entirely clear whether G proteins transit as heterotrimers, or as free Gα or Gβγ species. If the latter, one could easily envision that an escort factor would be required to transit Gα (and Gβγ) to the proper intracellular membranes lest it signal inappropriately during transport. Small G proteins including Ras and Rab homologues share this type of membrane cycling principle. Rab GTPases utilize a combination of soluble GDI, GEF, and “escort” factors to shuttle unlipidated Rabs throughout the cell, present Rabs to the lipidation machinery, and target the lipidated Rabs to the correct cellular membrane compartment (Ali and Seabra 2005).

Given the known in vitro biochemical function of Ric-8 proteins as soluble G protein α subunit GEFs, it is a challenge, although conceivable, to envision a role for Ric-8 protein involvement in any one of these G protein subunit trafficking or biosynthetic processes. In this context, Ric-8 “GEF activity” could serve simply as a mechanism to regulate Gα:Ric-8 binding/dissociation. In this highly prospective role, Ric-8 would bind Gα subunits (either nascent chains, or mature membrane Gα) and traffic/escort the Ric-8:Gα nucleotide-free complex to the proper destination (the Golgi, or Gβγ on the ER or plasma membrane). At the destination, Ric-8 would be invoked to stimulate GTP binding to Gα and release an activated-Gα species. Gα would hydrolyze its bound GTP, return to the inactive state, and reassociate with Gβγ or GoLoco.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and PhysiologyUniversity of Rochester Medical CenterRochesterUSA