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 (βAR) 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 βAR regulation is subtype-specific with a rank order of β2AR > β1AR > β3AR. Differences between species are expected also because amino acid sequences differ. Uncoupling and down-regulation of βAR 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 βAR ligands used to promote livestock production. Pigs fed βAR 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 βAR 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 βAR 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 βAR ligand to compensate for the decline in response or to augment the ligand response by inhibiting the inhibitory G protein Gi.
Implications
Compensatory desensitization is a well-characterized response to chronically elevated agonist concentration that results in a net loss of beta-adrenergic receptors (βAR) from the plasma membrane and reduced tissue response. The ability of βAR agonists to affect pig growth and alter body composition may well be limited by βAR desensitization. Experimental approaches should be investigated to determine the extent to which desensitization limits drug response, and to develop practical approaches to optimize the effectiveness of exogenously administered compounds. Three βAR subtypes have been cloned from mammalian species and most tissues express more than one subtype. It is not known which βAR subtypes are linked to growth responses in the pig or how βAR agonists affect the balance of synthesis and degradation of each subtype in different tissues. Answers to these questions may lead to targeting strategies that improve the efficacy of βAR ligands.
Key Words: Beta-Adrenergic Receptor, Pigs, Regulation
© American Society of Animal Science. All rights reserved.
J. Anim. Sci. 80(E. Suppl. 1):E30-E35
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