It has been reported that keratinocytes possess phospholipase C (PLC)-mediated signal transduction system(s), that can be triggered by histamine, bradykinin, thrombin, platelet-activating factor (PAF), and epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha). Since the activation of PLC results in release of 1,2-diacylglycerol (DAG), the physiologic activator of protein kinase C (PKC) that modulates the epidermal adenylate cyclase, we investigated the effects of these PLC activating chemicals on the adenylate cyclase responses of dispase-separated normal pig epidermis. Among these chemicals and factors only histamine decreased the successive histamine-induced cyclic AMP accumulation and increased forskolin-, and cholera toxin-induced AMP accumulations. These effects were similar to those of PKC activators. However, in contrast to the PKC-activator-induced partial and receptor-non-specific desensitization, the histamine-induced desensitization was completely-inducible and specific to the histamine receptor system, and was not affected by the PKC inhibitor, H-7. Similar modulation of the epidermal adenylate cyclase was induced by other adenylate cyclase stimulators (epinephrine, adenosine and prostaglandin E2), but not by bradykinin, thrombin, PAF, or EGF. The combined addition of bradykinin, thrombin, PAF and EGF to the culture medium had no effect on the adenylate cyclase responses, either. Thus no evidence for receptor-agonist dependent PLC-induced modulation of the adenylate cyclase was obtained in the normal pig epidermis. Although keratinocytes might contain PLC-mediated signal transduction systems, that are triggered by histamine, bradykinin, thrombin, PAF, and EGF/TGF-alpha, none of the activators singly or in combination appear to activate PKC sufficiently for the modulation of adenylate cyclase responses of the normal pig epidermis.