Ras proteins increase Ca(2+)-responsiveness of smooth muscle contraction

G-proteins may be involved in receptor-mediated Ca(2+)-sensitization of smooth muscle contraction, but the responsible G-proteins are not yet known. Here we show that in beta-escin skinned mesenteric microarteries, H-ras p21 proteins, preactivated with GTP or GTP gamma S, increase force at constant submaximal Ca2+ (pCa 6.3) concentration dependently. The GTP-bound form of the wild-type H-ras p21 and the oncogenic mutant (p21[G12V]) were equally effective. The nucleotide-free and the inactive GDP-bound form of ras p21 had no effect on force. The tryosine kinase inhibitor, tryphostin, partially reversed the effect of the ras proteins in the GTP-bound form on force. Thus, ras proteins mimic the Ca(2+)-sensitizing effect of GTP gamma S and vasoconstrictors in mesenteric microarteries which may involve tyrosine phosphorylation.