Regulation of the function of EGF receptors via P_2 purinergic receptors and related cell signaling systems

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We studied how stimulation of the purinergic receptors and other receptors (bradykinin receptors) elicites the cell signalling and affects other rceptors, e.g.the EGF receptor. We used A-431 human epidermoid carcinoma cells for the present experiment since they express high level of EGF receptors in addition to P_2 purinergic receptors. The stimulation of P_2 purinergic receptors stimulated PLC activity, followed by the PKC activation and [Ca^<2+>]_i elevation. From the ligand specificity to increase [Ca^<2+>]_i, the purinergic receptors responsible for provoking such cellular activity are suggested to be the P_<2Y> or P_<2U>-type. All the nucleotides that increased [Ca^<2+>]_i also inhibited the EGF receptor high affinity bindnig indicating that the function of EGF receptors is regulated by P_2 purinergic receptors via the cellular signal transduction system. The EGF high affinity binding was also inhibited when the cells were stimulated by bradykinin. However, the inhibition by bradykinin of the EGF high affinity binding was transient. Bradykinin was shown to stimulate a phosphoprotein phosphatase (s) as well as protein kinase C.Such biphasic effects of bradykinin to phosphorylate and dephosphorylate EGF receptors imply a homeostatic control of the receptor function in regulating phopshorylation level. In addition to PLC activation, stimulation by EGF and ATP activated either DG kinase or PLD which in turn supplied PA and activated PKC/ [Ca2+]i system, all of which were found to be essential for the stimulation of PI synthesis. The present results imply the general prospect that ligand stimulation, which mobilizes second messengers and consumes their precursors, simultaneously provokes the pathway to synthesize and salvage the second messenger precursors.