Relationship between lipolysis and cyclic AMP generation mediated by atypical beta-adrenoceptors in rat adipocytes

1 The nature of the beta-adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (-)-isoprenaline and the lipolytically selective beta-adrenoceptor agonist, BRL 37344, was investigated by use of the beta1-selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes.

2 While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (-)-isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62.

3 With CGP 20712A small rightward shifts of the (-)-isoprenaline concentration-response curve (CRC) were observed at concentrations up to 10-mu-M, while at 100-mu-M and 1mM clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10-mu-M. Only at 100-mu-M and 1mM CGP 20712A were rightward shifts observed.

4 CGP 20712A concentrations of 10-mu-M and 100-mu-M depressed the maximum of the (-)-isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (-)-isoprenaline). Only at 1 mM CGP 20712A, was the CRC of BRL 37344 depressed, while the (-)-isoprenaline maximum was diminished further.

5 It was concluded that as with lipolysis, (-)-isoprenaline acts both through typical beta-1- and atypical beta-3-adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical beta-3-adrenoceptors.

6 The results also demonstrate that the relationship between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (-)-isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (-)-isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.