Recently we demonstrated that the effects of β2-adrenoceptor (AR) stimulation to augment Ca2+ current (I(Ca)), cytosolic Ca2+ (Ca(i)) transients, and contractility in rat ventricular myocytes are largely dissociated from its effect to increase cellular CAMP levels. This result suggested that β2ARs might be coupled to signaling pathways other than the G(sa)-mediated activation of adenylyl cyclase. Here we show that pertussis toxin (PTX) pretreatment specifically potentiates the responses of rat heart cells to β2AR but not β1AR stimulation. After PTX pretreatment, 1) the dose-response curve for the effects of the β2AR agonist zinterol on contraction amplitude is shifted leftward and upward (EC50 changed from about 1.0 μM to 70 nM), 2) in indo-1-loaded cells, the maximal effects of zinterol (10-5 M) on Ca(i) transient and contraction amplitudes are additionally increased 1.7- and 2.0-fold, respectively, over those in control cells, and 3) the increase in I(Ca) amplitude induced by the same zinterol concentration is potentiated by 2.5-fold. Similar effects of PTX are observed when β2ARS are stimulated by isoproterenol in the presence of a selective β1AR blocker, CGP 20712A. All effects of β2AR agonists in both PTX- treated and control cells are abolished by a selective β2AR blocker, ICI 118,551. In contrast, neither the base-line I(Ca), Ca(i) transient, and contraction in the absence of βAR stimulation nor the β1AR-mediated augmentations of these parameters are significantly altered by PTX treatment. These results demonstrate, for the first time, that the G(s)-coupled β2AR can simultaneously activate a pathway that leads to functional inhibition in cardiac cells via a PTX-sensitive G protein. The activation of more than one G protein during β2AR stimulation, leading to functionally opposite effects, may provide a mechanism to protect the heart from Ca2+ overload and arrhythmias during the response to stress.
|Original language||English (US)|
|Number of pages||8|
|State||Published - 1995|
ASJC Scopus subject areas
- Molecular Medicine