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Its ability to contract and relax is essential for organ function. In vessels, vascular smooth muscle cells or arterial myocytes help regulate blood pressure and ensure proper blood flow to tissues. However, during diseases such as atherosclerosis, hypertension, and restenosis, these myocytes undergo a major transformation. They shift from a quiescent, contractile state to an active, synthetic one. In this synthetic state, they behave like inflammatory cells: secreting cytokines and signaling molecules, remodeling the surrounding matrix, and becoming migratory and proliferative. This shift is tied to a remodeling of their ion transport repertoire. Here, we build and refine a cohesive model whereby synthetic myocytes adopt a phenotype resembling nonexcitable cells. We propose that their ion transport toolkit changes as a coordinated unit, creating a distinct calcium signaling signature that supports their new roles in growth, movement, inflammation, and secretion, while sacrificing their contractile features. Focusing mainly on arterial myocytes, we examine how disease-driven changes in ion transport reshape the calcium signaling landscape. This shift moves away from classical excitation-contraction, mediated by L-type calcium channels and ryanodine receptors, and toward channels such as store-operated stromal interaction molecule (STIM)\/Orai and transient receptor potential (TRP) channels, which are activated by growth and vasoactive factors and operate best at hyperpolarized membrane potentials. We also explore the remodeling of ion channels, transporters, and pumps within internal organelles and emphasize how understanding these changes could reveal new therapeutic targets for treating disease.<\/jats:p>","DOI":"10.1152\/physrev.00031.2025","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T08:33:17Z","timestamp":1774686797000},"page":"1757-1835","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The nonexcitable smooth muscle: remodeling the smooth muscle ion transport toolkit in disease"],"prefix":"10.1152","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9831-796X","authenticated-orcid":false,"given":"Martin T.","family":"Johnson","sequence":"first","affiliation":[{"name":"Emory University School of Medicine","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6759-864X","authenticated-orcid":false,"given":"Mohamed","family":"Trebak","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, Pittsburgh, Pennsylvania, United States"},{"name":"University of Pittsburgh School of Medicine","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","unstructured":"da Vinci L.\n                      I manoscritti di Leonardo da Vinci della Reale biblioteca di Windsor: Dell\u2019anatomia, fogli B \/ pubblicati da Teodoro Sabachnikoff, transcritti ed annotati da Giovanni Piumati, con traduzione in lingua francese\n                      . 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