Model for leukocyte regulation by chemoattractant receptors: Roles of a guanine nucleotide regulatory protein and polyphosphoinositide metabolism

Binding of chemoattractants to their receptors on phagocytes activates a guanine nucleotide regulatory (N) protein through the substitution of GTP for GDP on N. The activated N protein in turn stimulates a membrane-associated phospholipase C by lowering the Ca²⁺ concentration required to activate this enzyme from supraphysiologic levels to ambient intracellular concentrations. The phospholipase C hydrolyzes phosphatidylinositol 4,5-bisphosphate into the Ca²⁺ mobilizer inositol 1,4,5-trisphosphate and the protein kinase C activator 1,2-diacylgycerol. In addition to promoting cellular activation, the products of this hydrolysis initiate processes which feed back to inhibit polyphosphoinositide breakdown. The regulatory model proposed herein may be relevant to other receptors which stimulate polyphosphoinositide metabolism.