TRP proteins: novel therapeutic targets for regional blood pressure control?

Abstract

Peripheral vascular resistance is controlled in large part by the sympathetic branch of the autonomic nervous system. In response to sensory input primarily via the vagus nerve, a change in sympathetic outflow alters the tone of the vascular tree via the release of catecholamines from nerve terminals present in the adventitial layer of the vessel wall and from chromaffin cells of the adrenal medulla. Through action at the α1-adrenergic receptor (α1-AR) present on the surface of vascular smooth muscle cells (SMCs), catecholamines increase contraction, constrict blood vessels, and, thus, cause an increase in mean arterial pressure. As in cardiac and skeletal muscle, a rise in cytosolic free Ca2+ concentration ([Ca2+]i) triggers contraction of vascular SMCs. Stimulation of α1-ARs causes an increase in [Ca2+]i through several different mechanisms.1 2 First, α1-AR is a member of the heptahelical receptor family, which activates phospholipase C (PLC) via a GTP-binding protein, Gq. Activation of PLC causes the production of 2 second messengers, inositol-1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol (DAG). Ins(1,4,5)P3 causes the release of Ca2+ from the endoplasmic reticulum, resulting in a rapid but transient increase in [Ca2+]i. DAG is primarily thought to activate protein kinase C but may also play a more direct role in activating Ca2+ entry (see below). In many types of SMCs, receptor stimulation is associated with activation of nonselective cation channels (NSCCs) that may allow Ca2+ to enter the cell from the extracellular space. Perhaps more importantly, the activation of an NSCC will tend to depolarize the SMC, which in turn will activate voltage-dependent Ca2+ channels (VDCCs), allowing additional Ca2+ influx. The importance of VDCCs to vascular smooth muscle contraction is …