Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation.

Divya Guntur,Horst Olschewski,Péter Enyedi,Réka Csáki,Chandran Nagaraj,Andrea Olschewski

doi:10.3390/biom11111629

Abstract

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options.

Highlights

Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, Austria; Department of Physiology, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, Hungary; Abstract: Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell0 s membrane potential and the tone in the vessels
Potent relaxing and contracting agents produced and released by endothelial and circulating cells, control the tone of the adjacent smooth muscle cells. All these local or circulating stimuli frequently act on different K+ channels of endothelial and smooth muscle cells, underpinning the crucial role of these unique membrane structures in the pulmonary circulation [1,2]
This review focuses on the contribution of the large conductance calcium (Ca2+ )

Summary

Ang II

Peroxisome proliferator activated recetor; cAMP: Cyclic adenosine monophosphate; PKA: Protein c-srci:A.Tyrosine kinase src (inactivated); GSH: Glutatione; NADH: Reduced adenine kinase. The S0 segment is unique to the BKCa channel and builds the extracellular N-terminus responsible for binding to modulatory β-subunits. Another salient feature of this channel is the presence of the S7–S10 segments in the intracellular region—the C-terminus of the protein. S7–S10 is twice as long as the transmembrane part in terms of primary amino acid sequence and the last two segments S9 and S10 have a highly conserved inter-species sequence This C-terminus creates a tetrameric gating ring containing two high-affinity Ca2+ binding sites. Recent allosteric modulations assume four modular voltage sensors and four Ca2+ binding sites [43] Activation of these sensors can independently lead to channel opening and communication between the sensors and the pore and between sensors. Representative patch-clamp recordings of K+ofcurrents in primary humanhuman pulmonary microvascular endothelial

Representative patch-clamp recordings

The Role of the α-Subunit in the Pulmonary Circulation

Findings

Perspective