Protein phosphorylation signaling mechanisms in carotid body chemoreception.

Abstract

Chemotransduction in the carotid body occurs in specialized type I cells and likely involves a complex series of regulated events which culminates in the release of neurotransmitter agents and the excitation of afferent nerve fibers. Previous studies have shown that multiple factors, including the levels of calcium and cyclic nucleotide second messengers, are important regulators of the chemoreceptor transduction cascade in type I cells. In addition, increases in electrical excitability induced in type I cells by chronic exposure to hypoxia are mimicked by agents which elevate intracellular cyclic AMP levels [Stea et al., J Neurosci 1995;15:2192-2202]. These and other findings suggest that protein kinases, and the phosphorylation of specific protein targets are important components of the hypoxic transduction machinery. Moreover, protein kinase-mediated cascades may participate in the well-known physiological adjustments which occur in the carotid body during prolonged stimulation. In the current study, our data demonstrate (1) the presence of specific protein kinases and target phosphoproteins in the carotid body, and also in the morphologically similar small intensely fluorescent cells of the superior cervical sympathetic ganglia. (2) Nitric oxide production and efferent inhibition in the chemosensory tissue is reduced in the presence of the specific tyrosine kinase inhibitor, lavendustin A. (3) Hypoxia-induced catecholamine release from type I cells is inhibited by the protein kinase A antagonist, Rp-cAMPs. And finally (4), exposure to chronic hypoxia up-regulates the expression of the tyrosine kinase, fyn, and an important growth regulatory phosphoprotein, growth associated protein-43 (GAP-43). These findings suggest that second messenger-mediated phosphorylation and dephosphorylation of specific protein targets is a mechanism capable of regulating diverse cellular functions in the carotid body during acute and chronic stimulation.