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      Twik‐2 −/− mouse demonstrates pulmonary vascular heterogeneity in intracellular pathways for vasocontractility


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          We have previously shown Twik‐2 −/− mice develop pulmonary hypertension and vascular remodeling. We hypothesized that distal pulmonary arteries (D‐ PAs) of the Twik‐2 −/− mice are hypercontractile under physiological venous conditions due to altered electrophysiologic properties between the conduit and resistance vessels in the pulmonary vascular bed. We measured resting membrane potential and intracellular calcium through Fura‐2 in freshly digested pulmonary artery smooth muscles ( PASMCs) from both the right main ( RMPA) and D‐ PA (distal) regions of pulmonary artery from WT and Twik‐2 −/− mice. Whole segments of RMPAs and D‐ PAs from 20 to 24‐week‐old wildtype ( WT) and Twik‐2 −/− mice were also pressurized between two glass micropipettes and bathed in buffer with either arterial or venous conditions. Abluminally‐applied phenylephrine ( PE) and U46619 were added to the buffer at log increments and vessel diameter was measured. All values were expressed as averages with ± SEM. Vasoconstrictor responses did not differ between WT and Twik‐2 −/− RMPAs under arterial conditions. Under venous conditions, Twik‐2 −/− RMPAs showed an increased sensitivity to PE with a lower EC50 ( P = 0.02). Under venous conditions, Twik‐2 −/− D‐ PAs showed an increase maximal vasoconstrictor response to both phenylephrine and U46619 compared to the WT mice ( P < 0.05). Isolated PASMCs from Twik‐2 −/− D‐ PA were depolarized and had higher intracellular calcium levels compared to PASMCs from RMPA of both WT and Twik‐2 −/− mice. These studies suggest that hypercontractile responses and electrophysiologic properties unique to the anatomic location of the D‐ PAs may contribute to pulmonary hypertensive vasculopathy.

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          Molecular background of leak K+ currents: two-pore domain potassium channels.

          Two-pore domain K(+) (K(2P)) channels give rise to leak (also called background) K(+) currents. The well-known role of background K(+) currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K(2P) channel types) that this primary hyperpolarizing action is not performed passively. The K(2P) channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K(2P) channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K(2P) channel family into the spotlight. In this review, we focus on the physiological roles of K(2P) channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.
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            A novel channelopathy in pulmonary arterial hypertension.

            Pulmonary arterial hypertension is a devastating disease with high mortality. Familial cases of pulmonary arterial hypertension are usually characterized by autosomal dominant transmission with reduced penetrance, and some familial cases have unknown genetic causes. We studied a family in which multiple members had pulmonary arterial hypertension without identifiable mutations in any of the genes known to be associated with the disease, including BMPR2, ALK1, ENG, SMAD9, and CAV1. Three family members were studied with whole-exome sequencing. Additional patients with familial or idiopathic pulmonary arterial hypertension were screened for the mutations in the gene that was identified on whole-exome sequencing. All variants were expressed in COS-7 cells, and channel function was studied by means of patch-clamp analysis. We identified a novel heterozygous missense variant c.608 G→A (G203D) in KCNK3 (the gene encoding potassium channel subfamily K, member 3) as a disease-causing candidate gene in the family. Five additional heterozygous missense variants in KCNK3 were independently identified in 92 unrelated patients with familial pulmonary arterial hypertension and 230 patients with idiopathic pulmonary arterial hypertension. We used in silico bioinformatic tools to predict that all six novel variants would be damaging. Electrophysiological studies of the channel indicated that all these missense mutations resulted in loss of function, and the reduction in the potassium-channel current was remedied by the application of the phospholipase inhibitor ONO-RS-082. Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (Funded by the National Institutes of Health.)
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              Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension.

              Mutations in the KCNK3 gene have been identified in some patients suffering from heritable pulmonary arterial hypertension (PAH). KCNK3 encodes an outward rectifier K(+) channel, and each identified mutation leads to a loss of function. However, the pathophysiological role of potassium channel subfamily K member 3 (KCNK3) in PAH is unclear. We hypothesized that loss of function of KCNK3 is a hallmark of idiopathic and heritable PAH and contributes to dysfunction of pulmonary artery smooth muscle cells and pulmonary artery endothelial cells, leading to pulmonary artery remodeling: consequently, restoring KCNK3 function could alleviate experimental pulmonary hypertension (PH).

                Author and article information

                Physiol Rep
                Physiol Rep
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                10 January 2019
                January 2019
                : 7
                : 1 ( doiID: 10.1002/phy2.2019.7.issue-1 )
                : e13950
                [ 1 ] Baylor College of Medicine Houston Texas
                [ 2 ] Texas Children’s Hospital Houston Texas
                [ 3 ] University of Texas‐Houston McGovern Medical School Houston Texas
                [ 4 ] Michael E.DeBakey Veterans Affairs Medical Center Houston Texas
                Author notes
                [*] [* ] Correspondence

                Lavannya M. Pandit, 2002 Holcombe Blvd., Pulm Suite 3A‐314, Houston, TX 77030.

                Tel: 713‐794‐7961

                Fax: 713‐794‐7316

                E‐mail: Lpandit@ 123456bcm.edu

                © 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 01 October 2018
                : 06 November 2018
                : 15 November 2018
                Page count
                Figures: 6, Tables: 0, Pages: 9, Words: 5041
                Funded by: United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service
                Award ID: IK2BX002410
                Membrane Physiology
                Pulmonary Circulation
                Cardiovascular Physiology
                Muscle Contraction and Relaxation
                Smooth Muscle
                Original Research
                Original Research
                Custom metadata
                January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:11.01.2019

                potassium channels,pulmonary artery smooth muscle cells,pulmonary hypertension,vasocontractility


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