A variety of receptors coupled to the heterotrimeric guanine nucleotide-binding protein G q/11 stimulate intracellular Ca 2+ release through inositol (1,4,5)-trisphosphate (IP 3 ) formation. We previously reported that tyrosine phosphorylation of the a subunit of the G q/11 protein by protein tyrosine kinases (PTKs) regulates the activation of G q/11 protein. Here we show that protein tyrosine phosphatases (PTPs) are also essential for G q/11 protein activation. We ®nd that G q/11 protein-coupled receptor-mediated formation of IP 3 is blocked by PTP inhibitors as well as PTK inhibitors. These inhibitors act prior to G q/11 protein activation. Tyrosine phosphorylation of the a subunit of G q/11 appears to inhibit its interaction with receptors. Thus, PTP is required for controlling the level of tyrosine phosphorylation of the a subunit of G q/11 to promote its interaction with receptors. Therefore, we conclude that PTKs and PTPs co-operate to proceed activation cycle of the G q/11 protein through tyrosine phosphorylation and de-phosphorylation of the a subunit of G q/11 .