Functional Interaction among KCa and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease

Abstract

Effective delivery of oxygen and essential nutrients to vital organs and tissues throughout the body requires adequate blood flow supplied through resistance vessels. The intimate relationship between intracellular calcium ([Ca2+]i) and regulation of membrane potential (Vm) is indispensable for maintaining blood flow regulation. In particular, Ca2+-activated K+ (KCa) channels were ascertained as transducers of elevated [Ca2+]i signals into hyperpolarization of Vm as a pathway for decreasing vascular resistance, thereby enhancing blood flow. Recent evidence also supports the reverse role for KCa channels, in which they facilitate Ca2+ influx into the cell interior through open non-selective cation (e.g., transient receptor potential; TRP) channels in accord with robust electrical (hyperpolarization) and concentration (~20,000-fold) transmembrane gradients for Ca2+. Such an arrangement supports a feed-forward activation of Vm hyperpolarization while potentially boosting production of nitric oxide. Furthermore, in vascular types expressing TRP channels but deficient in functional KCa channels (e.g., collecting lymphatic endothelium), there are profound alterations such as downstream depolarizing ionic fluxes and the absence of dynamic hyperpolarizing events. Altogether, this review is a refined set of evidence-based perspectives focused on the role of the endothelial KCa and TRP channels throughout multiple experimental animal models and vascular types. We discuss the diverse interactions among KCa and TRP channels to integrate Ca2+, oxidative, and electrical signaling in the context of cardiovascular physiology and pathology. Building from a foundation of cellular biophysical data throughout a wide and diverse compilation of significant discoveries, a translational narrative is provided for readers toward the treatment and prevention of chronic, age-related cardiovascular disease.

Modulation of Cardiovascular Function in Primary Hypertension in Rat by SKA-31, an Activator of KCa2.x and KCa3.1 Channels

“…Using arterial pressure myograph, other investigators have demonstrated SKA-31-evoked inhibition of myogenic tone in rat cremaster, middle cerebral arteries [19], and mesenteric arteries [20] in normotensive animals while hypertensive Cx40- or K Ca 3.1 -deficient mice were not affected by the eNOS inhibitor l -NAME. Differences in NO involvement in K Ca channel activator-mediated effects might result from experimental procedures and/or nature of the vasoconstrictor stimulus used [42,43]. Thus, it has been recently suggested, that a link between K Ca channel-mediated hyperpolarization and NO production in regulation of smooth muscle cell contractility exists [42,44].…”

Elementary calcium signaling in arterial smooth muscle

“…Further work is necessary to study the changes these molecules undergo during aging. Recent evidence also supports the reverse role for BK Ca channels, in which they facilitate Ca 2+ influx into the cell interior through open nonselective cation (e.g., transient receptor potential; TRP) channels in accord with robust electrical (hyperpolarization) and concentration (~20,000-fold) transmembrane gradients for Ca 2+ [131]. Such an arrangement supports a feed-forward activation of membrane hyperpolarization while potentially affecting Ca 2+ spark-BK Ca channel coupling.…”

<p>Exercise restores impaired endothelium-derived hyperpolarizing factor–mediated vasodilation in aged rat aortic arteries via the TRPV4-K_Ca2.3 signaling complex</p>

“…Accumulating evidence suggests that Ca 2+ -activated potassium channels may interact with Ca 2+ -permeable transient receptor potential channels to generate signal transduction between these channels in the vasculature 19. For example, TRPC1 is physically associated with BK Ca in vascular smooth muscle cells, and Ca 2+ entry via TRPC1 activates BK Ca to cause membrane hyperpolarization 20.…”