Gz signaling: emerging divergence from Gi signaling

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 Gi subfamily. All members of the Gi subfamily, with the sole exception of Gz, are substrates for the pertussis toxin ADP-ribosyl transferase. Gz also exhibits unique biochemical and regulatory properties. Initial portrayals of the cellular functions of Gz bear high resemblance to those of other Gi proteins both in terms of the receptors and effectors linked to Gz. However, recent discoveries have begun to insinuate a distinct role for Gz in cellular communication. Functional interactions of the α subunit of Gz (Gαz) with the NKR-P1 receptor, Gαz-specific regulator of G protein signaling, p21-activated kinase, G protein-regulated inducers of neurite outgrowth, and the Eya2 transcription cofactor have been demonstrated. These findings provide possible links for Gz to participate in cellular development, survival, proliferation, differentiation and even apoptosis. In this review, we have drawn a sketch of a signaling network with Gz as the centerpiece. The emerging picture is one that distinguishes Gz from other members of the Gi subfamily.