β₂-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 β₁- and β₂-adrenergic receptors (AR) are present in rat ventricular myocytes, but stimulation of these receptor subtypes elicits qualitatively different cellular responses (Xiao, R.-P., and Lakatta, E. G. (1993) Circ. Res. 73, 286-300). In the present study, the biochemical mechanism underlying the distinct βAR subtype actions have been investigated. Although both β₁AR and β₂AR stimulation increased total cellular cAMP in suspensions of rat ventricular myocytes to a similar extent, the maximum elevation of the membrane bound cAMP by β₂AR stimulation was only half of that induced by β₁AR stimulation, suggesting that stimulation the βAR subtypes leads to different compartmentation of cAMP. The effects of β₁AR 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 kinetics closely paralleled the increase in cAMP. In contrast, the increase in both membrane bound and total cAMP content after β₂AR stimulation were completely dissociated from the effects of β₂AR stimulation to increase the amplitudes of cytosolic Ca²⁺ transient and contraction. Furthermore, β₂AR stimulation did not phosphorylate phospholamban to the same extent as did β₁AR stimulation. This finding provides a mechanism for the failure of β₂AR stimulation to accelerate the kinetics of the Ca²⁺_i, (cytosolic Ca²⁺) transient and contraction. These results indicate that the effects of β₂AR stimulation on Ca²⁺, transient and contraction are uncoupled from the cAMP production and cAMP-dependent protein phosphorylation and indicate that, in addition to coupling to adenylate cyclase, β₂AR stimulation also activates other signal transduction pathway(s) to produce changes in cytosolic Ca²⁺ and contraction.