Relationship between lipolysis and cyclic AMP generation mediated by atypical β‐adrenoceptors in rat adipocytes

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Abstract
The nature of the β‐adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (−)‐isoprenaline and the lipolytically selective β‐adrenoceptor agonist, BRL 37344, was investigated by use of the β1‐selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes. 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. With CGP 20712A small rightward shifts of the (−)‐isoprenaline concentration‐response curve (CRC) were observed at concentrations up to 10 μm, while at 100 μm and 1 mm clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10 μm. Only at 100 μm and 1mm CGP 20712A were rightward shifts observed. CGP 20712A concentrations of 10 μm and 100 μm 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. It was concluded that as with lipolysis, (−)‐isoprenaline acts both through typical β1‐ and atypical β3‐adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical β3‐adrenoceptors. 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.