Differential recruitment and differential regulation by physiological amines of fat cell β-1, β-2 and β-3 adrenergic receptors expressed in native fat cells and in transfected cell lines

Why are there so many adrenoceptor subtypes

CLASSIFICATION of receptor systems which are activated by sympathomimetic amines has engaged the attention of many investigators. Ahlquist1–3 has suggested the convenient designations of alpha (α) and beta (β) to distinguish major differences in the responses elicited in various organ systems. Our investigations have provided results which cannot be explained easily on the assumption that the β-type designates a single receptor population4–6. We now report additional studies which show that two distinct receptor types are at present included within this group.

Differentiation of receptor systems activated by sympathomimetic amines

The beta(1)-adrenergic receptor (beta(1)-AR) plays a key role in regulating heart rate and contractility in response to catecholamines. Our studies have focused on defining the factors that regulate the expression of the beta(1)-AR gene. We determined that a 65-base-pair (bp) region in the beta(1)-AR promoter between bp -394 and bp -330 directs basal transcription. An element located between -377 and -365 can bind Sp1 and Sp3. In Drosophila melanogaster SL2 cells, Sp1 stimulated the expression of the beta(1)-AR promoter, whereas Sp3 was unable to activate transcription. Site-directed mutagenesis indicated that an intact Sp1-binding site is essential for maintaining the activity of the basal promoter. In addition to binding Sp family members, the nucleotides between -381 and -367 can bind the zinc-finger transcription factor Egr-1. The Egr-1 and Sp1 binding sites are partially overlapping and their binding sequence is conserved among mammalian beta(1)-AR genes. The induction of Egr-1 in rat neonatal ventricular myocytes with phorbol-12-myristate-13-acetate or in HeLa S3 cells by regulated expression of Egr-1 in a tetracycline-responsive promoter, suppressed expression from the beta(1)-AR promoter. Overexpression of Sp1 in SK-N-MC cells increased beta(1)-AR mRNA by 2.4-fold, whereas overexpression of Egr-1 reduced beta(1)-AR mRNA by 40%. Coexpression of Egr-1 with Sp1 reduced Sp1-mediated up-regulation of beta(1)-AR mRNA by 60%. Mutagenesis revealed that an intact Sp1-binding site is essential for observing transcriptional repression by Egr-1 and that Egr-1 suppressed the transcription of the beta(1)-AR gene by competing with Sp1 for binding to their overlapping sites. These results reveal a novel physiologically relevant transcriptional mechanism for reciprocal regulation of beta(1)-AR gene expression.

Reciprocal Regulation of β1-Adrenergic Receptor Gene Transcription by Sp1 and Early Growth Response Gene 1: Induction of EGR-1 Inhibits the Expression of the β1-Adrenergic Receptor Gene

Transcription of the rat beta 1-adrenergic receptor gene. Characterization of the transcript and identification of important sequences.

A β1-adrenergic receptor (β1AR) clone, designated Clone 5, was isolated from a BALB/c mouse liver genomic library screened at low stringency with a human brain β2AR cDNA probe. Sequence an...

Characterization of a Mouse β1-Adrenergic Receptor Genomic Clone

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Characterization of a Mouse β1-Adrenergic Receptor Genomic Clone