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  • Introduction Heterotrimeric G proteins mediate signal transd

    2023-11-17

    Introduction Heterotrimeric Gαβγ proteins mediate signal transduction through seven-transmembrane domain receptors. In response to neurotransmitters or hormones, activated receptors bind GTP via the Gα subunit leading to the dissociation of Gα from the Gβγ dimer. G proteins regulate the levels of second messengers (e.g. cyclic nucleotides and phospholipids) which in turn modulate the activities of downstream effectors (such as ion Necrostatin 2 and enzymes) in the nervous system. G protein signaling has been extensively analyzed in C. elegans in recent years to try to understand how G protein complexes function in vivo. In the nervous system of C. elegans, different heterotrimeric G proteins signaling pathways have characteristic effects on development, neural degeneration and behavior, including locomotion, egg laying and defecation (Bargmann and Kaplan, 1998). Locomotion and egg laying activity in C. elegans are controlled by the antagonistic effects of the Gαq/EGL-30 and Gαo/GOA-1 signaling pathways (Brundage et al., 1996, Hajdu-Cronin et al., 1999). This Gαq/Gαo network can regulate synaptic transmission via several downstream effectors including UNC-13, a DAG binding protein that modulates synaptic vesicle release (Lackner et al., 1999, Miller et al., 1999, Nurrish et al., 1999). The antagonistic activities of the Gα subunits EGL-30 and GOA-1 are in turn regulated by Gβγ complexes. Necrostatin 2 Genetic analyses have shown that GPB-2, the second Gβ subunit of the nematode, interacts with both EGL-10 and EAT-16 RGS (Regulator of G protein Signaling) proteins to modulate locomotion and egg laying. Upon binding of the ligand to its receptor, GPB-2/RGS is released by its cognate Gα and the complex can then bind and inhibit the opposing Gα by enhancing its GTPase activity (Robatzek et al., 2001, Van den Linden et al., 2001). The RIC-8 protein is also a component of the G protein network. It acts upstream of Gαq, and it is linked to the Gαs pathway (Miller et al., 2000, Schade et al., 2005, Reynolds et al., 2005). In early C. elegans embryos, the Gβ subunit GPB-1 is required for correct centrosome migration around the nucleus and thus plays a role in orienting the mitotic spindle (Zwaal et al., 1996). In parallel, two Gα subunits, GOA-1 and GPA-16, control spindle asymmetry (Ahringer, 2003). Nuclear migration is crucial for axis determination, and there is evidence that centrosomes and various motor proteins associated with the microtubule cytoskeleton are required to position nuclei at specific locations in the cytoplasm. ric-8 is also involved in spindle morphology and position, but its role in this process still remains to be determined. Moreover, the par (partitioning defective) genes are required for the establishment and maintenance of anterio-posterior (A/P) body asymmetry after fertilization (Rose and Kemphues, 1998). Although recent data also indicate that PAR polarity proteins and heterotrimeric G protein signaling regulate the stability of microtubules at the cortex of the embryo (Labbé et al., 2003), targets of heterotrimeric G proteins have not been identified yet. Beside G proteins, other molecules including let-99 and spn-1 may also be involved in regulating centrosome position, but their role in this pathway is not clear (Rose and Kemphues, 1998). G protein function is regulated by different classes of proteins, and signaling through the βγ heterodimer is modulated by binding to members of the Phosducin (Pd) and Phosducin-like Protein (PhLP) family (Gaudet et al., 1996, Thibault et al., 1997). Pd and PhLP are highly homologous acidic phosphoproteins. Pd has a well-characterized role in retinal signal transduction, while PhLP is considered to be a potentially ubiquitous regulator of Gβγ signaling. Several studies have established that the physiological control of G protein function by PhLP involves phosphorylation by casein kinase II and calcium/calmodulin kinase II (Thulin et al., 2001, Humrich et al., 2003). The dephosphorylated form of PhLP binds Gβγ which then prevents receptor-mediated Gα reactivation and blocks interactions between Gβγ and its effectors (Yoshida et al., 1994). PhLP has multiple partners: it can bind p45/SUG-1, the regulatory subunit of the 26S proteasome, and it regulates protein folding through interaction with the cytosolic chaperonin CCT (Barhite et al., 1998, Martin Benito et al., 2004). PhLP also interacts with 14.3.3 proteins in brain extracts (Garzon et al., 2002). Multiple 14.3.3 isoforms play roles in numerous cellular processes including signal transduction. Previous studies have shown that 14.3.3 can protect its target protein from proteolysis and dephosphorylation. It has been suggested that, in retinal photoreceptors, 14.3.3 proteins inhibit binding of Pd to Gβγ by sequestering phosphorylated Pd molecules (Nakano et al., 2001). In C. elegans, two 14.3.3 genes, par-5 and ftt-2, have been reported, but only PAR-5 acts in gonads and early embryos (Morton et al., 2002).