{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:09:02Z","timestamp":1775624942193,"version":"3.50.1"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2020\u201300908, to KS, 2009\u20131039 and 2018\u201302635"],"award-info":[{"award-number":["2020\u201300908, to KS, 2009\u20131039 and 2018\u201302635"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001729","name":"Swedish Foundation for Strategic Research","doi-asserted-by":"publisher","award":["IRC15-0067"],"award-info":[{"award-number":["IRC15-0067"]}],"id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>\n                    Myocardin-related transcription factors (MRTFs: myocardin\/\n                    <jats:italic>MYOCD<\/jats:italic>\n                    , MRTF-A\/\n                    <jats:italic>MRTFA<\/jats:italic>\n                    , and MRTF-B\/\n                    <jats:italic>MRTFB<\/jats:italic>\n                    ) are co-factors of serum response factor (SRF) that activate the smooth muscle cell (SMC) gene program and that play roles in cardiovascular development and mechanobiology. Gain and loss of function experiments have defined the SMC gene program under control of MRTFs, yet full understanding of their impact is lacking. In the present study, we tested the hypothesis that the muscarinic M\n                    <jats:sub>3<\/jats:sub>\n                    receptor (\n                    <jats:italic>CHRM3<\/jats:italic>\n                    ) is regulated by MRTFs together with SRF. Forced expression of MYOCD (8d) in human coronary artery (SMC) followed by RNA-sequencing showed increased levels of M\n                    <jats:sub>2<\/jats:sub>\n                    , M\n                    <jats:sub>3<\/jats:sub>\n                    , and M\n                    <jats:sub>5<\/jats:sub>\n                    receptors (\n                    <jats:italic>CHRM2<\/jats:italic>\n                    : 2-fold,\n                    <jats:italic>CHRM3<\/jats:italic>\n                    : 16-fold, and\n                    <jats:italic>CHRM5<\/jats:italic>\n                    : 2-fold). The effect of MYOCD on M\n                    <jats:sub>3<\/jats:sub>\n                    was confirmed by RT-qPCR using both coronary artery and urinary bladder SMCs, and correlation analyses using human transcriptomic datasets suggested that M\n                    <jats:sub>3<\/jats:sub>\n                    may also be regulated by MRTF-B. Head-to-head comparisons of MYOCD, MRTF-A and MRTF-B, argued that while all MRTFs are effective, MRTF-B is the most powerful transactivator of\n                    <jats:italic>CHRM3<\/jats:italic>\n                    , causing a 600-fold increase at 120h. Accordingly, MRTF-B conferred responsiveness to the muscarinic agonist carbachol in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging experiments. M\n                    <jats:sub>3<\/jats:sub>\n                    was suppressed on treatment with the MRTF-SRF inhibitor CCG-1423 using SMCs transduced with either MRTF-A or MRTF-B and using intact mouse esophagus in culture (by 92\u00b12%). Moreover, silencing of SRF with a short hairpin reduced\n                    <jats:italic>CHRM3<\/jats:italic>\n                    (by &amp;gt;60%) in parallel with \u03b1-actin (\n                    <jats:italic>ACTA2<\/jats:italic>\n                    ). Tamoxifen inducible knockout of Srf in smooth muscle reduced\n                    <jats:italic>Srf<\/jats:italic>\n                    (by 54\u00b14%) and\n                    <jats:italic>Chrm3<\/jats:italic>\n                    (by 41\u00b16%) in the urinary bladder at 10days, but\n                    <jats:italic>Srf<\/jats:italic>\n                    was much less reduced or unchanged in aorta, ileum, colon, trachea, and esophagus. Longer induction (21d) further accentuated the reduction of\n                    <jats:italic>Chrm3<\/jats:italic>\n                    in the bladder and ileum, but no change was seen in the aorta. Single cell RNA-sequencing revealed that\n                    <jats:italic>Mrtfb<\/jats:italic>\n                    dominates in ECs, while\n                    <jats:italic>Myocd<\/jats:italic>\n                    dominates in SMCs, raising the possibility that\n                    <jats:italic>Chrm3<\/jats:italic>\n                    may be driven by Mrtfb-Srf in the endothelium and by Myocd-Srf in SMCs. These findings define a novel transcriptional control mechanism for muscarinic M\n                    <jats:sub>3<\/jats:sub>\n                    receptors in human cells, and in mice, that could be targeted for therapy.\n                  <\/jats:p>","DOI":"10.3389\/fphys.2021.710968","type":"journal-article","created":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T06:14:46Z","timestamp":1630736086000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Regulation of the Muscarinic M3 Receptor by Myocardin-Related Transcription Factors"],"prefix":"10.3389","volume":"12","author":[{"given":"Li","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catarina","family":"Rippe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ola","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmytro","family":"Kryvokhyzha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Ekman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Sw\u00e4rd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1053\/j.gastro.2007.08.078","article-title":"Severe intestinal obstruction on induced smooth muscle-specific ablation of the transcription factor SRF in adult mice","volume":"133","author":"Angstenberger","year":"2007","journal-title":"Gastroenterology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3826","DOI":"10.1016\/j.bmcl.2013.04.080","article-title":"Optimization of novel nipecotic bis(amide) inhibitors of the Rho\/MKL1\/SRF transcriptional pathway as potential anti-metastasis agents","volume":"23","author":"Bell","year":"2013","journal-title":"Bioorg. 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