Functional roles of γ2, γ3 and γ4, three new Ca2+ channel subunits, in P/Q-type Ca2+ channel expressed in Xenopus oocytes

1. Stargazin or gamma (2), the product of the gene mutated, in the stargazer mouse, is a homologue of the gamma (1) protein, an accessory subunit of the skeletal muscle L-type Ca2+ channel. gamma (2) is selectively-expressed in the brain, and considered to be a putative neuronal Ca2+ channel subunit based mainly on homology to gamma (1). Two new members of the gamma family expressed in the brain have recently been identified: gamma (3) and gamma (4). 2. We have co-expressed, in Xenopus oocytes, the human gamma (2), gamma (3) and gamma (4) subunits with the P/Q-type (Ca(V)2.1) Ca2+ channel and differ ent regulatory subunits (alpha (2)-delta; beta (1), beta (2), beta (3) or beta (4)). 3. Subcellular distribution of the gamma subunits confirmed their membrane localization. 4. Ba2+ currents, recorded using two-electrode voltage clamp, showed that the effects of the gamma subunits on the electrophysiological properties of the channel are, most of the time, minor. However, a fraction of the oocytes expressing beta subunits displayed an unusual slow-inactivating Ba2+ current. Expression of both beta and gamma subunits increased the appearance of the slow-inactivating current. 5. Our data support a role for the gamma subunit as a brain Ca2+ channel modulatory subunit and suggest that beta and gamma subunits are involved in a switch between two regulatory modes of the P/Q-type channel inactivation.