Preliminary data from the PI's laboratory has demonstrated that activation of alpha-1 adrenergic receptors inhibits beta-adrenergic induced stimulation of cardiac ion channels, particularly the C1 channel. The project proposed to extend these observations to other ion channels and to delineate the mechanisms involved. The proposal has 3 specific aims: (1) The PI will determine if alpha-1 adrenergic activation inhibits beta-stimulation in a similar fashion for C1 currents, L-type Ca currents and delayed rectified K currents. (2) It will be determined if alpha-1 adrenergic stimulation exerts its effects by changing cAMP production or degradation or by interactions involving the beta receptor itself, such as facilitating receptor desensitizations (3) The pathway involved in these effects will be delineated by identifying the subtype of alpha-adrenergic receptor involved, assessing pertussis toxin sensitivity and investigating the possible roles of phospholipase C, phospholipase A2 and tyrosine kinases.
