A farnesyltransferase inhibitor attenuated beta-adrenergic receptor downregulation in rat skeletal muscle.
Farnesylation represents an essential posttranslational modification of several well-defined proteins implicated in the homologous desensitization of the beta-adrenergic receptor (beta-ADR). The following study examined the effect of a novel farnesyltransferase inhibitor, BMS-191563, on agonist-mediated beta-ADR downregulation in skeletal muscle. Female Sprague-Dawley rats were treated for 12 days with the beta2-adrenergic agonist clenbuterol (4 mg/kg) with or without the concurrent administration of BMS-191563 (2 mg x kg(-1) x day(-1)). Clenbuterol promoted gastrocnemius muscle hypertrophy, whereas the soleus muscle was unaffected. Total beta-ADR density was decreased by 45 and 40% in the soleus and medial gastrocnemius (MG), respectively, after clenbuterol treatment. BMS-191563 treatment did not prevent clenbuterol-stimulated MG hypertrophy, but markedly attenuated beta-ADR downregulation in both muscle types. This latter effect in the soleus muscle was not associated with the inhibition of Ras farnesylation. Likewise, in rat cardiac fibroblasts, isoproterenol-mediated decrease of total beta-ADR density was abrogated by the prior treatment with BMS-191563. Collectively, these data demonstrate that the mechanism(s) implicated in agonist-mediated beta-ADR downregulation was sensitive to BMS-191563, thereby suggesting the involvement of farnesylated proteins.
Lavoie
Julie L
JL
Département de Kinésiologie, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
Calderone
Angelino
A
Béliveau
Louise
L
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000502:physiology; D002478:Cells, Cultured; D002976:Clenbuterol / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006984:Hypertrophy; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000294:innervation; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D017368:Protein Prenylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D002976:Clenbuterol