A NUCLEAR PATHWAY FOR ALPHA(1)-ADRENERGIC RECEPTOR SIGNALING IN CARDIAC-CELLS

Alpha1-adrenergic agonists and antagonists constitute an important cla ss of therapeutic agents commonly used for the treatment of various ca rdiovascular diseases like hypertension, congestive heart failure and supraventricular tachycardia. At the heart level, activation of alpha1 -adrenergic receptors is associated with marked morphological and gene tic changes. These include enhancement of contractility, myocardial gr owth (hypertrophy) and release of the heart major secretory product, a trial natriuretic factor (ANF). However, the signal transduction pathw ays which link extracellular activation of the receptors to cellular a nd genetic changes are not well understood. Using primary cardiocyte c ultures from neonate rat hearts, an alpha1-adrenergic regulatory seque nce has been identified in the 5' flanking region of the ANF gene. Thi s sequence, which is necessary and sufficient for transcriptional acti vation in response to the alpha1-specific agonist phenylephrine, inter acts with novel zinc-dependent proteins which are induced by alpha1-ad renergic stimulation. Consistent with a conserved regulatory mechanism , the alpha1 response element is highly conserved between rodent, bovi ne and human ANF genes, and is also present in the promoter region of other alpha1-responsive cardiac genes. The identification of a nuclear pathway for alpha1-receptor signaling will be useful for elucidating the intracellular effectors of alpha1-adrenergic receptors.