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However, the relative contributions of decreased cytosolic K+ concentration versus increased cytosolic Ca2+ concentration ([Ca2+]) remain disputed and incompletely defined. We investigated roles for elevated cytosolic [Ca2+] in NLRP3 activation and downstream inflammasome signaling responses in primary murine dendritic cells and macrophages in response to two canonical NLRP3 agonists (ATP and nigericin) that facilitate primary K+ efflux by mechanistically distinct pathways or the lysosome-destabilizing agonist Leu-Leu-O-methyl ester. The study provides three major findings relevant to this unresolved area of NLRP3 regulation. First, increased cytosolic [Ca2+] was neither a necessary nor sufficient signal for the NLRP3 inflammasome cascade during activation by endogenous ATP-gated P2X7 receptor channels, the exogenous bacterial ionophore nigericin, or the lysosomotropic agent Leu-Leu-O-methyl ester. Second, agonists for three Ca2+-mobilizing G protein\u2013coupled receptors (formyl peptide receptor, P2Y2 purinergic receptor, and calcium-sensing receptor) expressed in murine dendritic cells were ineffective as activators of rapidly induced NLRP3 signaling when directly compared with the K+ efflux agonists. Third, the intracellular Ca2+ buffer, BAPTA, and the channel blocker, 2-aminoethoxydiphenyl borate, widely used reagents for disruption of Ca2+-dependent signaling pathways, strongly suppressed nigericin-induced NLRP3 inflammasome signaling via mechanisms dissociated from their canonical or expected effects on Ca2+ homeostasis. The results indicate that the ability of K+ efflux agonists to activate NLRP3 inflammasome signaling can be dissociated from changes in cytosolic [Ca2+] as a necessary or sufficient signal.<\/jats:p>","DOI":"10.4049\/jimmunol.1402658","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T22:03:23Z","timestamp":1426111403000},"page":"3937-3952","source":"Crossref","is-referenced-by-count":275,"title":["K+ Efflux Agonists Induce NLRP3 Inflammasome Activation Independently of Ca2+ Signaling"],"prefix":"10.1093","volume":"194","author":[{"given":"Michael A","family":"Katsnelson","sequence":"first","affiliation":[{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L Graham","family":"Rucker","sequence":"additional","affiliation":[{"name":"The Ohio State University College of Medicine , Columbus, OH 43210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana M","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George R","family":"Dubyak","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Case Western Reserve University , Cleveland, OH 44106"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,4,15]]},"reference":[{"key":"2025030706014793500_r1","first-page":"251","volume-title":"Williams Hematology","author":"Warren","year":"2010","edition":"8th Ed"},{"key":"2025030706014793500_r2","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"2025030706014793500_r3","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/j.1600-065X.2011.01046.x","article-title":"The inflammasome: an integrated view","volume":"243","author":"Gross","year":"2011","journal-title":"Immunol. 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