{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:52:15Z","timestamp":1790815935764,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      G protein\u2010gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain and heart, and are present in the adrenal cortex. GIRK4 (\n                      <jats:italic>KCNJ5<\/jats:italic>\n                      ) subunits are abundant in the heart and adrenal cortex. Multiple mutations of\n                      <jats:italic>KCNJ5<\/jats:italic>\n                      cause primary aldosteronism (PA). Mutations in the pore region of GIRK4 cause loss of K\n                      <jats:sup>+<\/jats:sup>\n                      selectivity, Na\n                      <jats:sup>+<\/jats:sup>\n                      influx and depolarization of zona glomerulosa cells followed by hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore. We expressed aldosteronism\u2010linked GIRK4\n                      <jats:sub>R52H<\/jats:sub>\n                      , GIRK4\n                      <jats:sub>E246K<\/jats:sub>\n                      and GIRK4\n                      <jats:sub>G247R<\/jats:sub>\n                      mutants in\n                      <jats:italic>Xenopus<\/jats:italic>\n                      oocytes. Whole\u2010cell currents of heterotetrameric GIRK1\/4\n                      <jats:sub>R52H<\/jats:sub>\n                      and GIRK1\/4\n                      <jats:sub>E246K<\/jats:sub>\n                      channels were greatly reduced compared with GIRK1\/4\n                      <jats:sub>WT<\/jats:sub>\n                      . Nevertheless, all heterotetrameric mutants retained full K\n                      <jats:sup>+<\/jats:sup>\n                      selectivity and inward rectification. When expressed as homotetramers, only GIRK4\n                      <jats:sub>WT<\/jats:sub>\n                      , but none of the mutants, produced whole\u2010cell currents. Confocal imaging, single\u2010channel and F\u00f6rster Resonance Energy Transfer (FRET) analyses showed: (1) reduction of membrane abundance of all mutated channels, especially as homotetramers, (2) impaired interaction with G\u03b2\u03b3 subunits, and (3) reduced open probability of GIRK1\/4\n                      <jats:sub>R52H<\/jats:sub>\n                      . VU0529331, a GIRK4 opener, activated homotetrameric GIRK4\n                      <jats:sub>G247R<\/jats:sub>\n                      channels, but not GIRK4\n                      <jats:sub>R52H<\/jats:sub>\n                      or GIRK4\n                      <jats:sub>E246K<\/jats:sub>\n                      . In the human adrenocortical carcinoma cell line (HAC15), VU0529331 and overexpression of heterotetrameric GIRK1\/4\n                      <jats:sub>WT<\/jats:sub>\n                      , but not overexpression of GIRK1\/4 mutants, reduced aldosterone secretion. Our results suggest that, contrary to pore mutants of GIRK4, non\u2010pore mutants R52H and E246K mutants are loss\u2010of\u2010function rather than gain\u2010of\u2010function\/selectivity\u2010loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N\u2010 and C\u2010terminal mutations.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp14938-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            Mutations in GIRK4 (\n                            <jats:italic>KCNJ5<\/jats:italic>\n                            ) G protein\u2010gated channels cause primary aldosteronism, a major cause of secondary hypertension. The primary mechanism is believed to be loss of K\n                            <jats:sup>+<\/jats:sup>\n                            selectivity.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            R52H and E246K, aldosteronism\u2010causing mutations in cytosolic N\u2010 and C\u2010 termini of GIRK4, were reported to cause loss of K\n                            <jats:sup>+<\/jats:sup>\n                            selectivity.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            We show that R52H, E246K and G247R mutations render homotetrameric GIRK channels non\u2010functional. In heterotetrameric context with GIRK1, these mutations impair membrane expression, interaction with G\u03b2\u03b3 and open probability, but do not alter K\n                            <jats:sup>+<\/jats:sup>\n                            selectivity or inward rectification.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            In the human aldosterone\u2010secreting cell line, a GIRK4 opener and overexpression of heterotetrameric GIRK1\/4\n                            <jats:sub>WT<\/jats:sub>\n                            , but not overexpression of GIRK1\/4 mutants, reduced aldosterone secretion.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Aldosteronism\u2010causing mutations in the cytosolic domain of GIRK4 are loss\u2010of\u2010function mutations rather than gain\u2010of\u2010function, selectivity\u2010loss mutations. Deciphering of exact biophysical mechanism that impairs the channel is crucial for setting the course of treatment.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp282690","type":"journal-article","created":{"date-parts":[[2021,12,26]],"date-time":"2021-12-26T21:18:32Z","timestamp":1640553512000},"page":"1419-1437","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A revised mechanism of action of hyperaldosteronism\u2010linked mutations in cytosolic domains of GIRK4 (KCNJ5)"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1322-4906","authenticated-orcid":false,"given":"Boris","family":"Shalomov","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology School of Medicine and Sagol School of Neuroscience Tel Aviv University  Tel 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