Calcineurin is part of a negative feedback loop in the InsP3/Ca²⁺ signalling pathway in blowfly salivary glands.

The ubiquitous InsP3/Ca(2+) signalling pathway is modulated by diverse mechanisms, i.e. feedback of Ca(2+) and interactions with other signalling pathways. In the salivary glands of the blowfly Calliphora vicina, the hormone serotonin (5-HT) causes a parallel rise in intracellular [Ca(2+)] and [cAMP] via two types of 5-HT receptors. We have shown recently that cAMP/protein kinase A (PKA) sensitizes InsP3-induced Ca(2+) release. We have now identified the protein phosphatase that counteracts the effect of PKA on 5-HT-induced InsP3/Ca(2+) signalling. We demonstrate that (1) tautomycin and okadaic acid, inhibitors of protein phosphatases PP1 and PP2A, have no effect on 5-HT-induced Ca(2+) signals; (2) cyclosporin A and FK506, inhibitors of Ca(2+)/calmodulin-activated protein phosphatase calcineurin, cause an increase in the frequency of 5-HT-induced Ca(2+) oscillations; (3) the sensitizing effect of cyclosporin A on 5-HT-induced Ca(2+) responses does not involve Ca(2+) entry into the cells; (4) cyclosporin A increases InsP3-dependent Ca(2+) release; (5) inhibition of PKA abolishes the effect of cyclosporin A on the 5-HT-induced Ca(2+) responses, indicating that PKA and calcineurin act antagonistically on the InsP3/Ca(2+) signalling pathway. These findings suggest that calcineurin provides a negative feedback on InsP3/Ca(2+) signalling in blowfly salivary glands, counteracting the effect of PKA and desensitizing the signalling cascade at higher 5-HT concentrations.