Ca2+/calmodulin-gated small- and intermediate-conductance Kcachannels in cardiovascular regulation: Targets for novel pharmacological treatments

Abstract

In vascular biology, the Ca 2+/calmodulin-gated K + channels, K Ca3.1 and K Ca2.3, produce membrane hyperpolarization in response to Ca 2+ mobilization events and thereby initiate endothelium-derived hyperpolarization (EDH)-type of arterial dilation. The physiological relevance of this system in-vivo is evidenced by the observation that genetically encoded loss of K Ca3.1 and K Ca2.3 caused channelsubtype specifi c cardiovascular phenotypes characterized by endothelial dysfunction to receptor stimulation or mechanical stress and blood pressure alterations. From the translational perspective, K Ca3.1 and K Ca2.3 dysfunctions are a feature of idiopathic cardiovascular disease, chronic infl ammation, atherosclerosis and organ fi brosis and K Ca2.3 has been implicated in atrial fi brillation. Accordingly, K Ca3.1 and K Ca2.3 emerge as possible drug targets. In this chapter, we would like to highlight our recent advances in K Ca3.1 and K Ca2 biology, pharmacology, as well as consequences of pharmacological manipulating K Ca3.1 and K Ca2.3 for systemic cardiovascular regulation and cardiovascular health. Moreover, we explore impacts of innovative channel modulators on cardiac function, physical activity and behavior in keeping with the expression of K Ca2-subtypes in the heart and neurons.