[
Prog Mol Biol Transl Sci,
2009]
The nematode worm, Caenorhabditis elegans, contains orthologs of most regulator of G protein signaling (RGS) protein subfamilies and all four G protein -subunit subfamilies found in mammals. Every C. elegans RGS and G gene has been knocked out, and the in vivo functions and G targets of a number of RGS proteins have been characterized in detail. This has revealed a complex relationship between the RGS and G proteins, in which multiple RGS proteins can regulate the same G protein, either by acting redundantly or by exerting control over signaling under different circumstances or in different cells. RGS proteins that are coexpressed can also show specificity for distinct G targets in vivo, and the determinants of such specificity can reside outside of the RGS domain. This review will discuss how analysis in C. elegans may aid us in achieving a full understanding of the physiological functions of RGS proteins.
[
Trends Pharmacol Sci,
2009]
RGS (regulator of G protein signaling) proteins have emerged as crucial regulators, effectors and integrators in G-protein-coupled receptor (GPCR) signaling networks. Many RGS proteins accelerate GTP hydrolysis by Galpha subunits, thereby regulating G protein activity, whereas certain RGS proteins also transduce Galpha signals to downstream targets. Particularly intriguing are members of the RGS7 (R7) family (RGS6, RGS7, RGS9 and RGS11), which heterodimerize with Gbeta5. In Caenorhabditis elegans, R7-Gbeta5 heterodimers regulate synaptic transmission, anesthetic action and behavior. In vertebrates, they regulate vision, postnatal development, working memory and the action of psychostimulants or morphine. Here we highlight R9AP and R7BP, a related pair of recently identified SNARE-like R7-family binding proteins, which regulate intracellular trafficking, expression and function of R7-Gbeta5 heterodimers in retina and brain. Emerging understanding of R7BP and R9AP promises to provide new insights into neuronal GPCR signaling mechanisms relevant to the causes and treatment of neurological disorders.
[
WormBook,
2006]
Heterotrimeric G proteins, composed of alpha , beta , and gamma subunits, are able to transduce signals from membrane receptors to a wide variety of intracellular effectors. In this role, G proteins effectively function as dimers since the signal is communicated either by the G alpha subunit or the stable G betagamma complex. When inactive, G alpha -GDP associates with G betagamma and the cytoplasmic portion of the receptor. Ligand activation of the receptor stimulates an exchange of GTP for GDP resulting in the active signaling molecules G alpha -GTP and free G betagamma , either of which can interact with effectors. Hydrolysis of GTP restores G alpha -GDP, which then reassociates with G betagamma and receptor to terminate signaling. The rate of G protein activation can be enhanced by the guanine-nucleotide exchange factor, RIC-8 , while the rate of GTP hydrolysis can be enhanced by RGS proteins such as EGL-10 and EAT-16 . Evidence for a receptor-independent G-protein-signaling pathway has been demonstrated in C. elegans early embryogenesis. In this pathway, the G alpha subunits GOA-1 and GPA-16 are apparently activated by the non-transmembrane proteins GPR-1 , GPR-2 , and RIC-8 , and negatively regulated by RGS-7 . The C. elegans genome encodes 21 G alpha , 2 G beta and 2 G gamma subunits. The alpha subunits include one ortholog of each mammalian G alpha family: GSA-1 (Gs), GOA-1 (Gi/o), EGL-30 (Gq) and GPA-12 (G12). The remaining C. elegans alpha subunits ( GPA-1 , GPA-2 , GPA-3 , GPA-4 , GPA-5 , GPA-6 , GPA-7 , GPA-8 , GPA-9 , GPA-10 , GPA-11 , GPA-13 , GPA-14 , GPA-15 , GPA-16 , GPA-17 and ODR-3 ) are most similar to the Gi/o family, but do not share sufficient homology to allow classification. The conserved G alpha subunits, with the exception of GPA-12 , are expressed broadly while 14 of the new G alpha genes are expressed in subsets of chemosensory neurons. Consistent with their expression patterns, the conserved C. elegans alpha subunits, GSA-1 , GOA-1 and EGL-30 are involved in diverse and fundamental aspects of development and behavior. GOA-1 acts redundantly with GPA-16 in positioning of the mitotic spindle in early embryos. EGL-30 and GSA-1 are required for viability starting from the first larval stage. In addition to their roles in development and behaviors such as egg laying and locomotion, the EGL-30 , GSA-1 and GOA-1 pathways interact in a network to regulate acetylcholine release by the ventral cord motor neurons. EGL-30 provides the core signals for vesicle release, GOA-1 negatively regulates the EGL-30 pathway, and GSA-1 modulates this pathway, perhaps by providing positional cues. Constitutively activated GPA-12 affects pharyngeal pumping. The G alpha subunits unique to C. elegans are primarily involved in chemosensation. The G beta subunit, GPB-1 , as well as the G gamma subunit, GPC-2 , appear to function along with the alpha subunits in the classic G protein heterotrimer. The remaining G beta subunit, GPB-2 , is thought to regulate the function of certain RGS proteins, while the remaining G gamma subunit, GPC-1 , has a restricted role in chemosensation. The functional difference for most G protein pathways in C. elegans, therefore, resides in the alpha subunit. Many cells in C. elegans express multiple G alpha subunits, and multiple G protein pathways are known to function in specific cell types. For example, Go, Gq and Gs-mediated signaling occurs in the ventral cord motor neurons. Similarly, certain amphid neurons use multiple G protein pathways to both positively and negatively regulate chemosensation. C. elegans thus provides a powerful model for the study of interactions between and regulation of G protein signaling.
[
Biochem Soc Trans,
2007]
The nematode Caenorhabditis elegans contains over 20 genes for TRP (transient receptor potential) channels which include members of all of the subclasses identified in mammalian cells. These proteins include three members of the TRPM (TRP melastatin) family:
gon-2 (abnormal gonad development),
gtl-1 (
gon-2-like 1) and
gtl-2. Although studies of these genes are at an early stage, we are beginning to understand their functions in the life of C. elegans. Mutations in
gon-2 have defective gonad formation because of failures in the cell division of the somatic gonad precursor cells.
gon-2 and
gtl-1 are both expressed in the intestine of the animal. Experiments on
gon-2,
gtl-1 double mutants show that they have a severe growth defect that is ameliorated by the addition of high levels of Mg(2+) to the growth medium.
gon-2,
gtl-1 double mutants have defective magnesium homoeostasis and also have altered sensitivity to toxic levels of Ni(2+). Furthermore
gon-2 mutants have reduced levels of I(ORCa) (outwardly rectifying calcium current) in the intestinal cells. Thus these two channels appear to play an important role in cation homoeostasis in C. elegans. In addition, perturbing the function of
gon-2 and
gtl-1 disrupts the ultradian defecation rhythm in C. elegans, suggesting that these channels play an important role in regulating this calcium-dependent rhythmic process. The tractability of C. elegans as an experimental animal and its amenability to techniques such as RNAi (RNA interference) and in vivo imaging make it an excellent system for an integrative analysis of TRPM function.
[
Biochimica et Biophysica Acta,
2004]
Proteins belonging to the Bcl-2 family function as regulators of 'life-or-death' decisions in response to various intrinsic and extrinsic stimuli. In mammals, cell death is controlled by pro- and anti-apoptotic members of the Bcl-2 family, which function upstream of the caspase cascade. Structural and functional homologues of the Bcl-2 family proteins also exist in lower eukaryotes, such as nematodes and flies. In nematodes, an anti-apoptotic Bcl-2 family protein, CED-9, functions as a potent cell death inhibitor, and a BH3-only protein, EGL-1, acts as an inhibitor of CED-9 to facilitate the spatio-temporal regulation of programmed cell death. On the other hand, the Drosophila genome encodes two Bcl-2 family proteins, Drob-1/Debcl/dBorg-1/dBok and Buffy/dBorg-2, both of which structurally belong to the pro-apoptotic group, despite abundant similarities in the cell death mechanisms between flies and vertebrates. Drob-1 acts as a pro-apoptotic factor in vitro and in vivo, and Buffy/dBorg-2 exhibits a weak anti-apoptotic function. The ancestral role of the Bcl-2 family protein may be pro-apoptotic, and the evolution of the functions of this family of proteins may be closely linked with the contribution of mitochondria to the cell death pathway.