14th International Congress
THE "NEW FRONTIERS"
OF ARRHYTHMIAS 2000

Jan. 29 - Feb. 5, 2000
Marilleva, Trento, Italy

RT-30

Roles of b1 and b2 adrenergic receptors in L-type calcium current

Zsolt Nagykaldi, David Kem, Ralph Lazzara, Bela Szabo.
University of Oklahoma, USA

Discussion

In canine myocytes, selective stimulation of b₂ AR does not effect I_CaL⁶, an observation that might suggest that there is no direct coupling of b₂ AR transduction system with the L-type calcium channels. However, stimulation of b₂ AR has a relatively potent conditioning effect that augments the action of b₁ AR to increase I_CaL. This enhancing conditioning effect is not achieved if b₂ AR stimulation occurs after b₁ AR stimulation. Enhancement of the action of forskolin by b₂ AR stimulation indicates that the conditioning effect represents an action on adenylate cyclase (AC) to produce a change in the molecule that enhances its activity when AC is activated by b1 AR stimulation. There may be separate binding sites for the a subunits of stimulatory G protein translocated by b₁ AR versus b₂ AR, which when simultaneously bound by b₁ AR activated Gsa and b₂ AR activated Gsa molecules make AC more active.

The data indicate that the biphasic response to the natural agonist, NE, represents b₁ AR stimulation at lower concentrations and b₂ AR enhancement of b₁ AR stimulation at higher concentrations. b₂ AR stimulation may enhance I_CaL when AC activity is higher during phosphodiesterase inhibition but this action is abolished with b₁ AR antagonism. This finding suggests a basal level of b₁ AR activation in the absence of agonists, that responds to b₂ AR stimulation.

The physiological effects of this interaction would be to enhance the maximum effect of the natural agonists, NE, but also to extend by 1-2 orders of magnitude the physiological response to NE. The range of concentrations from minimal to maximal response for the balanced agonist ISO was approximately one order of magnitude while the range for the predominant a agonist, NE, was close to 3 orders of magnitude. This allows finer tuning of the response by the natural neurotransmitter NE.