The functional roles subserved by Gαz, a G protein α subunit found predominantly in neuronal tissues, have remained largely undefined. Here, we report that Gαz coupled neurotransmitter receptors to N-type Ca2+ channels when transiently overexpressed in rat sympathetic neurons. The Gαz-mediated inhibition was voltage dependent and PTX insensitive. Recovery from Gαz-mediated inhibition was extremely slow but accelerated by coexpression with RGS proteins. Gαz selectively interacted with a subset of receptors that ordinarily couple to N-type Ca2+ channels via PTX-sensitive Go/i proteins. In addition, Gαz rescued the activation of heterologously expressed GIRK channels in PTX-treated neurons. These results suggest that Gαz is capable of coupling receptors to ion channels and might underlie PTX-insensitive ion channel modulation observed in neurons under physiological and pathological conditions.