G²γ dimers stimulate vascular L‐type Ca 2+ channels via phosphoinositide 3‐kinase

We have previously reported that, in venous myocytes, G²γ scavengers inhibit angiotensin AT 1A receptor‐induced stimulation of L‐type Ca 2+ channels (1). Here, we demonstrate that intracellular infusion of purified G²γ complexes stimulates the L‐type Ca 2+ channel current in a concentration‐dependent manner. Additional intracellular dialysis of GDP‐bound inactive Gα o or of a peptide corresponding to the G²γ binding region of the ²‐adrenergic receptor kinase completely inhibited the G²γ‐induced stimulation of Ca 2+ channel currents. The gating properties of the channel were not affected by intracellular application of G²γ, suggesting that G²γ increased the whole‐cell calcium conductance. In addition, both the angiotensin AT 1A receptor‐ and the G²γ‐induced stimulation of L‐type Ca 2+ channels were blocked by pretreatment of the cells with wortmannin, at nanomolar concentrations. Correspondingly, intracellular infusion of an enzymatically active purified recombinant G²γ‐sensitive phosphoinositide 3‐kinase, PI3Kγ, mimicked G²γ‐induced stimulation of Ca 2+ channels. Both G²γ‐ and PI3Kγ‐induced stimulations of Ca 2+ channel currents were reduced by protein kinase C inhibitors suggesting that the G²γ/PI3Kγ‐activated transduction pathway involves a protein kinase C. These results indicate for the first time that G²γ dimers stimulate the vascular L‐type Ca 2+ channels through a G²γ‐sensitive PI3K.— Viard, P., Exner, T., Maier, U., Mironneau, J., Nürnberg, B., Macrez, N. G²γ dimers stimulate vascular L‐type Ca 2+ channels via phosphoinositide 3‐kinase γ. FASEB J. 13, 685–694 (1999)