Receptor-Mediated Signal Transduction and Cell Signaling

Abstract

The maintenance of low resistance, pressure, and tone in the pulmonary circulation is dependent on the interaction of circulating and locally produced vasomodulatory regulators; many such vasoactive mediators act via receptor-mediated signaling pathways. Many types of receptors that regulate pulmonary vascular tone are expressed on the plasma membrane of cells, although vasomotor activity is also influenced by intracellular receptors, such as calcium-release receptors and receptors that regulate transcription (e.g., steroid hormone receptors). The pulmonary vasculature expresses a wide variety of receptor classes and subtypes that facilitate the interaction of cells of the pulmonary circulation with their extracellular environment (hormones, neurotransmitters, and other factors in the extracellular milieu play key roles in modifying blood flow under both physiological and patho-physiological conditions). One can identify such receptors by assessing the binding of radioligands, molecular cloning and expression studies, antisense approaches, and/or by conducting studies with transgenic or knockout animals. Receptor-mediated signaling in the pulmonary circulation changes with development and disease, is highly species specific, cell-type specific, and often depends on an intact endothelium. Moreover, the accessibility of plasma membrane receptors for neurotransmitters and hormones from the extracellular environment makes them excellent drug targets. The major classes of membrane receptors that regulate pulmonary vascular tone are G-protein-coupled receptors, ligand-gated ion channels, and receptor protein kinases [receptor tyrosine kinase and serine/threonine kinase receptors]. This chapter provides an overview of signaling by cell-surface receptors in the pulmonary circulation and highlights mediators whose activation regulates pulmonary vascular development, tone, and permeability.