G Protein α Subunit Gαz Couples Neurotransmitter Receptors to Ion Channels in Sympathetic Neurons

of these ion channels. In sympathetic neurons, G␣ s me-One Guthrie Square diates a cholera toxin-sensitive modulation of the Ca 2ϩ Sayre, Pennsylvania 18840 channels via a voltage-dependent pathway (Zhu and Ikeda, 1994). In addition, ion channel modulation coupling via an unidentified pertussis toxin (PTX)–insen-Summary sitive G␣ has been reported. For instance, the modulation of N-type Ca 2ϩ channels by norepinephrine (NE) The functional roles subserved by G␣ z , a G protein ␣ and prostaglandin E 2 (PGE 2) in sympathetic neurons is subunit found predominantly in neuronal tissues, have partially mediated by PTX-insensitive G proteins in a remained largely undefined. Here, we report that G␣ z voltage-dependent manner (Ikeda, 1992; Shapiro et al., coupled neurotransmitter receptors to N-type Ca 2؉ 1994). Neuronal K ϩ channels are also influenced by PTX-channels when transiently overexpressed in rat sym-insensitive G proteins (Nakajima et al., 1988). Among pathetic neurons. The G␣ z-mediated inhibition was the different families of PTX-insensitive G proteins (e.g., voltage dependent and PTX insensitive. Recovery from G␣ z , G q/11 ␣, and G 12 ␣), G␣ z has been suggested as a G␣ z-mediated inhibition was extremely slow but ac-potential candidate for mediating PTX-insensitive inhibi-celerated by coexpression with RGS proteins. G␣ z se-tion of ion channels (Casey et al., 1990; Fields and Casey, lectively interacted with a subset of receptors that 1997). To date, however, a functional role for G␣ z in ordinarily couple to N-type Ca 2؉ channels via PTX-modulating ion channels has not been established. sensitive G o/i proteins. In addition, G␣ z rescued the G␣ z is the sole member of the G i subfamily that lacks activation of heterologously expressed GIRK channels an ADP ribosylation site (i.e., cysteine four residues from in PTX-treated neurons. These results suggest that the carboxyl terminus) and is thus resistant to PTX. A G␣ z is capable of coupling receptors to ion channels cDNA encoding G␣ z has been isolated from a human and might underlie PTX-insensitive ion channel modu-retinal and rat brain cDNA library (Fong et al., 1988; lation observed in neurons under physiological and Maksuoka et al., 1988). Northern blot analyses and im-pathological conditions. munohistochemical studies have revealed that G␣ z is predominantly expressed in neuronal tissues such as intrinsic GTPase activity of G␣ z is extremely low. For Strathman and Simon, 1991). Receptor activation pro-instance, the hydrolysis rate for G␣ z is as much as 200-motes …