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Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a \u03b22 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.<\/jats:p>","DOI":"10.1085\/jgp.201912511","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T14:08:21Z","timestamp":1586873301000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles"],"prefix":"10.1085","volume":"152","author":[{"given":"Francine","family":"Uwera","sequence":"first","affiliation":[{"name":"University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tarek","family":"Ammar","sequence":"additional","affiliation":[{"name":"University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7265-7261","authenticated-orcid":true,"given":"Callum","family":"McRae","sequence":"additional","affiliation":[{"name":"University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada 1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0579-0358","authenticated-orcid":true,"given":"Lawrence J.","family":"Hayward","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Massachusetts Medical School, Worcester, MA 2"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-0677","authenticated-orcid":true,"given":"Jean-Marc","family":"Renaud","sequence":"additional","affiliation":[{"name":"University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, Ontario, Canada 1"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2020,4,14]]},"reference":[{"key":"2023072705582924600_bib1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1085\/jgp.201511476","article-title":"Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse","volume":"146","author":"Ammar","year":"2015","journal-title":"J. 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