DEPOLARIZATION AND NEUROTRANSMITTERS INCREASE NEURONAL PROTEIN-TYROSINE PHOSPHORYLATION

In rat hippocampal slices and in neurons in primary culture, K+-induce d depolarization increased markedly and rapidly tyrosine phosphorylati on of a 110-kDa protein (pp110)and, to a lesser degree, of a 120-kDa p rotein (pp120), in a calcium-dependent fashion. Glutamate, 1-aminocycl opentane-trans-1,3-dicarboxylic acid (an agonist of metabotropic gluta mate receptors), and lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropioni c acid (an agonist of ionotropic glutamate receptors) stimulated also tyrosine phosphorylation of pp110 and pp120. These effects were not ob served in astrocytes in primary culture. In hippocampal slices tyrosin e phosphorylation of pp110 and pp120 was stimulated by Ca2+-ionophores and by phorbol esters and antagonized by a chelator of intracellular Ca2+ and by drugs that inhibit protein kinase C. Stimulation of muscar inic and alpha(1)-adrenergic receptors increased also tyrosine phospho rylation of pp110 and pp120. These results demonstrate that membrane d epolarization and stimulation of neurotransmitter receptors activate a tyrosine phosphorylation pathway in neurons. This pathway involves an increase in intracellular Ca2+ concentrations and the activation of p rotein kinase C. It may provide a biochemical basis for some neurotrop hic effects of electrical activity and neurotransmitters and may contr ibute to the role of tyrosine phosphorylation in long-term potentiatio n.