BETA(2)-ADRENERGIC RECEPTOR-STIMULATED INCREASE IN CAMP IN RAT-HEART CELLS IS NOT COUPLED TO CHANGES IN CA2+ DYNAMICS, CONTRACTILITY, OR PHOSPHOLAMBAN PHOSPHORYLATION

Previous studies have Shown that both beta(1)- and beta(2)-adrenergic receptors (AR) are present in rat ventricular myocytes, but stimulatio n of these receptor subtypes elicits qualitatively different cellular responses (Xiao, R.-P., and Lakatta, E. G. (1993) Circ. Res. 73, 286-3 00). In the present study, the biochemical mechanism underlying the di stinct beta AR subtype actions have been investigated. Although both b eta(1)AR and beta(2)AR stimulation increased total cellular cAMP in su spensions of rat ventricular myocytes to a similar extent, the maximum elevation of the membrane bound cAMP by beta(2)AR stimulation was onl y half of that induced by beta(1)AR stimulation, suggesting that stimu lation the beta AR subtypes leads to different compartmentation of cAM P. The effects of beta(1)AR stimulation on Ca2+ transient (indexed by the transient increase in indo-1 fluorescence ration after excitation) and contraction amplitude (measured via photodiode array) and their k inetics closely paralleled the increase in cAMP. In contrast, the incr ease in both membrane bound and total cAMP content after beta(2)AR sti mulation were completely dissociated from the effects of beta(2)AR sti mulation to increase the amplitudes of cytosolic Ca2+ transient and co ntraction. Furthermore, beta(2)AR stimulation did not phosphorylate ph ospholamban to the same extent as did beta(1)AR stimulation. This find ing provides a mechanism for the failure of beta(2)AR stimulation to a ccelerate the kinetics of the Ca-i(2+) (cytosolic Ca2+) transient and contraction. These results indicate that the effects of beta(2)AR stim ulation on Ca-i(2+) transient and contraction are uncoupled from the c AMP production and cAMP-dependent protein phosphorylation and indicate that, in addition to coupling to adenylate cyclase, beta(2)AR stimula tion also activates other signal transduction pathway(s) to produce ch anges in cytosolic Ca2+ and contraction.