Abstract
α1-Adrenergic receptor (AR) subtypes in the heart are expressed by myocytes but not by fibroblasts, a feature that distinguishes α1-ARs from β-ARs. Here we studied myocyte-specific expression of α1-ARs, focusing on the subtype α1C (also called α1A), a subtype implicated in cardiac hypertrophic signaling in rat models. We first cloned the mouse α1C-AR gene, which consisted of two exons with an 18 kb intron, similar to the α1B-AR gene. The receptor coding sequence was >90% homologous to that of rat and human. α1C-AR transcription in mouse heart was initiated from a single Inr consensus sequence at −588 from the ATG; this and a putative polyadenylation sequence 8.5 kb 3′ could account for the predominant 11 kb α1C mRNA in mouse heart. A 5′-nontranscribed fragment of 4.4 kb was active as a promoter in cardiac myocytes but not in fibroblasts. Promoter activity in myocytes required a single muscle CAT (MCAT) element, and this MCAT bound in vitro to recombinant and endogenous transcriptional enhancer factor-1. Thus, α1C-AR transcription in cardiac myocytes shares MCAT dependence with other cardiac-specific genes, including the α- and β-myosin heavy chains, skeletal α-actin, and brain natriuretic peptide. However, the mouse α1C gene was not transcribed in the neonatal heart and was not activated by α1-AR and other hypertrophic agonists in rat myocytes, and thus differed from other MCAT-dependent genes and the rat α1C gene.
Footnotes
- Received August 29, 2000.
- Accepted January 17, 2001.
-
Send reprint requests to: Paul C. Simpson, M.D., VAMC 111-C-84150, Clement St., San Francisco, CA 94121. E-mail: pcs{at}itsa.ucsf.edu
-
↵1 Current address: Department of Medicine, University of Louisville, Louisville, Kentucky.
-
This work was supported by a Fellowship from the Cardiovascular Research Institute, the University of California, San Francisco (T32HL07731) (T.D.O.); a Fellowship from the American Heart Association, Western States Affiliate (D.G.R.); and the Department of Veterans Affairs and the National Institutes of Health (P.C.S.). The new cloned sequences reported herein have been submitted to GenBank under accession numbers AF362076, AF362077, and AF362078.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|