Gz signaling: emerging divergence from Gi signaling

Abstract

A large variety of neurotransmitters, hormones, and chemokines regulate cellular functions via cell surface receptors that are coupled to guanine nucleotide-binding regulatory proteins (G proteins) belonging to the G i subfamily. All members of the G i subfamily, with the sole exception of G z , are substrates for the pertussis toxin ADP-ribosyl transferase. G z also exhibits unique biochemical and regulatory properties. Initial portrayals of the cellular functions of G z bear high resemblance to those of other G i proteins both in terms of the receptors and eectors linked to G z . However, recent discoveries have begun to insinuate a distinct role for G z in cellular communication. Functional interactions of the a subunit of G z (Ga z ) with the NKR-P1 receptor, Ga z -speci®c regulator of G protein signaling, p21-activated kinase, G protein-regulated inducers of neurite outgrowth, and the Eya2 transcription cofactor have been demonstrated. These ®ndings provide possible links for G z to participate in cellular development, survival, proliferation, dierentiation and even apoptosis. In this review, we have drawn a sketch of a signaling network with G z as the centerpiece. The emerging picture is one that distinguishes G z from other members of the G i subfamily.

c-Src Is Activated by the Epidermal Growth Factor Receptor in a Pathway That Mediates JNK and ERK Activation by Gonadotropin-releasing Hormone in COS7 Cells

“…However, in the GnRHR-transfected COS7 cells we did not find any role for PKC in the activation of MAPKs, suggesting the involvement of other G proteins. To test the possible involvement of other G␣ isoforms we used pertussis toxin that serves as a selective inhibitor of G␣ i (54). The serum-starved GnRHR-transfected COS7 cells were pretreated with the toxin for 5 h, after which they were stimulated with GnRH-a and the phosphorylation of JNK, ERK, c-Src, and EGF receptor was FIG.…”

Novel somatic mutations in heterotrimeric G proteins in melanoma

“…10 Although the relationship between G-alpha z and the MAPK signaling pathway is not yet fully understood, there is evidence that G-alpha z might contribute to the regulation of specific subfamilies of MAPKs, including extracellular signal-regulated kinases and Jun N-terminal kinases. 11,12 Previous biochemical studies on GNAZ elucidating these relationships have not been conducted in cancer cells; however, as these signaling pathways are known to be important in cancer progression, future studies examining the impact of mutations in GNAZ in tumor cells are warranted.…”

RGSZ1 and GAIP Regulate μ- but Not δ-Opioid Receptors in Mouse CNS: Role in Tachyphylaxis and Acute Tolerance

“…The pertussis toxin-insensitive Gz transducer protein is regulated by a large number of receptors (Fields and Casey, 1997;Ho and Wong, 2001), leading to the inhibition of adenylyl cyclase activity (Wong et al, 1992) and the stimulation of K þ channels (Jeong and Ikeda, 1998). m-opioid receptors are described as regulating Gz proteins as well as Gi/o and Gq/11 proteins Standifer et al, 1996).…”

“…The Gz transducer protein shows features that greatly influence the quality of its regulatory activity on cellular effectors (Ho and Wong, 2001). In sharp contrast to Gai/o subunits, which are rather ubiquitously expressed, the expression of Gaz subunits is limited to the retina, brain, adrenal medulla, and platelets (Fong et al, 1988;Matsuoka et al, 1988;Gagnon et al, 1991).…”

“…The action of RGS proteins of the R4 subfamily causes Gi/o protein signaling to terminate rapidly (0.1-1 s) (Koelle, 1997;Berman and Gilman, 1998). Deactivation of Gz proteins is achieved specifically by the Rz subfamily of RGS proteins (Glick et al, 1998;Wang et al, 1998;Ho and Wong, 2001). Rz proteins bind GazGTP and increase the rate of hydrolysis by 200-400-fold, allowing the termination of signaling on a time scale of a few seconds (Glick et al, 1998;Wang et al, 1998).…”