Navegando por Palavras-chave "potassium channels"

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    The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery
    (Wiley, 2017) Bohnen, Michael S.; Roman-Campos, Danilo; Terrenoire, Cecile [UNIFESP]; Jnani, Jack; Sampson, Kevin J.; Chung, Wendy K.; Kass, Robert S.
    Background-Heterozygous loss of function mutations in the KCNK3 gene cause hereditary pulmonary arterial hypertension (PAH). KCNK3 encodes an acid-sensitive potassium channel, which contributes to the resting potential of human pulmonary artery smooth muscle cells. KCNK3 is widely expressed in the body, and dimerizes with other KCNK3 subunits, or the closely related, acid-sensitive KCNK9 channel. Methods and Results-We engineered homomeric and heterodimeric mutant and nonmutant KCNK3 channels associated with PAH. Using whole-cell patch-clamp electrophysiology in human pulmonary artery smooth muscle and COS7 cell lines, we determined that homomeric and heterodimeric mutant channels in heterozygous KCNK3 conditions lead to mutation-specific severity of channel dysfunction. Both wildtype and mutant KCNK3 channels were activated by ONO-RS-082 (10 mu mol/L), causing cell hyperpolarization. We observed robust gene expression of KCNK3 in healthy and familial PAH patient lungs, but no quantifiable expression of KCNK9, and demonstrated in functional studies that KCNK9 minimizes the impact of select KCNK3 mutations when the 2 channel subunits co-assemble. Conclusions-Heterozygous KCNK3 mutations in PAH lead to variable loss of channel function via distinct mechanisms. Homomeric and heterodimeric mutant KCNK3 channels represent novel therapeutic substrates in PAH. Pharmacological and pH-dependent activation of wildtype and mutant KCNK3 channels in pulmonary artery smooth muscle cells leads to membrane hyperpolarization. Co-assembly of KCNK3 with KCNK9 subunits may provide protection against KCNK3 loss of function in tissues where both KCNK9 and KCNK3 are expressed, contributing to the lung-specific phenotype observed clinically in patients with PAH because of KCNK3 mutations.
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    Impaired function of alpha-2 adrenoceptors in smooth muscle of mesenteric arteries from spontaneously hypertensive rats
    (Stockton Press, 1998-11-01) Feres, Teresa [UNIFESP]; Borges, Antonio Carlos Romao [UNIFESP]; Silva, Eneida de Gusmão [UNIFESP]; Paiva, Antonio Cechelli de Mattos [UNIFESP]; Paiva, Therezinha Bandiera [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    1 the alpha(2)-adrenoceptor function in mesenteric arteries of spontaneously hypertensive rats (SHR) was investigated by comparing membrane potential changes in response to adrenergic agonists in preparations from female SHR, Wistar-Kyoto (WKY) and normotensive Wistar rats (NWR).2 Resting membrane potential was found to be less negative in mesenteric arteries from SHR than in those from NWR and WKY. Apamin induced a decrease in the membrane potential of mesenteric artery rings without endothelium from NWR and WKY, but had no effects in those from SHR. Both UK 14,304 and adrenaline, in the presence of prazosin, induced a hyperpolarization that was significantly lower in de-endothelialized mesenteric rings from SHR than in those from NWR and WKY. in mesenteric rings with endothelium, however, similar hyperpolarization was observed in the three strains.3 in NWR mesenteric rings with endothelium the hyperpolarization induced by activation of alpha(2)-adrenoceptors was abolished by apamin, whereas in intact SHR mesenteric rings this hyperpolarization was slightly reduced by apamin and more efficiently reduced by N-omega-nitro-L-arginine.4 It is concluded that the activity of potassium channels coupled to alpha(2)-adrenoceptors is altered in the smooth muscle cells of SHR mesenteric arteries, contributing to their less negative membrane potential. On the other hand, the endothelial alpha(2)-receptors are functioning in mesenteric vessels from SHR and their stimulation induces a hyperpolarization mainly through the release of nitric oxide.