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Implications of feedback regulation of beta-adrenergic signaling¹

Department of Animal Science, Purdue University, West Lafayette, IN 47907

² Correspondence: Lilly Hall (phone: 765-494-4845; fax: 765-494-9346; E-mail: smills{at}purdue.edu).

Abstract

Receptor-mediated signals are tightly regulated by feedback inhibition and act to prevent signal overload and to reset the receptor to a changing environment. Short-term regulation (uncoupling) of beta-adrenergic receptors (ßAR) involves receptor phosphorylation and uncoupling of the receptor from the G protein Gs. Chronic exposure to ligand leads to reduced receptor number (down-regulation), which results from a combination of receptor internalization and degradation, and decreased mRNA abundance. The extent of ßAR regulation is subtype-specific with a rank order of ß2AR > ß1AR > ß3AR. Differences between species are expected also because amino acid sequences differ. Uncoupling and down-regulation of ßAR in pig tissues has been demonstrated in vivo and in vitro, although skeletal muscle exhibits a blunted response compared with adipose tissue and changes in mRNA abundance have not been observed. Desensitization presents a challenge clinically in the treatment of human disease and may well limit the effectiveness of ßAR ligands used to promote livestock production. Pigs fed ßAR ligands show a rapid response in growth and feed efficiency that tends to peak during the first 7 to 10 d but declines thereafter toward zero by approximately 6 wk. A similar pattern was reported in rats fed clenbuterol and was accompanied by a 50% reduction in ßAR in skeletal muscle. Feeding clenbuterol every 2nd d prevented the decline in the response to clenbuterol and gave a growth response that was equivalent to daily dosing. These data suggest that strategies to prevent or circumvent ßAR down-regulation may prolong the agonist response. Intermittent dosing of pigs may present logistical problems. An alternative approach may be to incrementally increase the dose of ßAR ligand to compensate for the decline in response or to augment the ligand response by inhibiting the inhibitory G protein Gi.

¹ Journal paper no. 16655 of the Purdue Univ. Agric. Res. Prog. This paper was presented at the 2001 Midwest meetings of the Am. Soc. Anim. Sci. [79 (Suppl. 2):53 (Abstr.)].

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