Potassium (K+) channels in the pulmonary vasculature: Implications in pulmonary hypertension Physiological, pathophysiological and pharmacological regulation

Abstract

The large K⁺ channel functional diversity in the pulmonary vasculature results from the multitude of genes expressed encoding K⁺ channels, alternative RNA splicing, the post-transcriptional modifications, the presence of homomeric or heteromeric assemblies of the pore-forming α-subunits and the existence of accessory β-subunits modulating the functional properties of the channel. K⁺ channels can also be regulated at multiple levels by different factors controlling channel activity, trafficking, recycling and degradation. The activity of these channels is the primary determinant of membrane potential (Em) in pulmonary artery smooth muscle cells (PASMC), providing an essential regulatory mechanism to dilate or contract pulmonary arteries (PA). K⁺ channels are also expressed in pulmonary artery endothelial cells (PAEC) where they control resting Em, Ca²⁺ entry and the production of different vasoactive factors. The activity of K⁺ channels is also important in regulating the population and phenotype of PASMC in the pulmonary vasculature, since they are involved in cell apoptosis, survival and proliferation. Notably, K⁺ channels play a major role in the development of pulmonary hypertension (PH). Impaired K⁺ channel activity in PH results from: 1) loss of function mutations, 2) downregulation of its expression, which involves transcription factors and microRNAs, or 3) decreased channel current as a result of increased vasoactive factors (e.g., hypoxia, 5-HT, endothelin-1 or thromboxane), exposure to drugs with channel-blocking properties, or by a reduction in factors that positively regulate K⁺ channel activity (e.g., NO and prostacyclin). Restoring K⁺ channel expression, its intracellular trafficking and the channel activity is an attractive therapeutic strategy in PH.

Keywords: Endothelium; Pharmacology; Potassium channels; Proliferation; Pulmonary hypertension; Smooth muscle.