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

Alpha1-adrenergic agonists and antagonists constitute an important class of therapeutic agents commonly used for the treatment of various cardiovascular diseases like hypertension, congestive heart failure and supraventricular tachycardia. At the heart level, activation of alpha1-adrenergic receptors is associated with marked morphological and genetic changes. These include enhancement of contractility, myocardial growth (hypertrophy) and release of the heart major secretory product, atrial natriuretic factor (ANF). However, the signal transduction pathways which link extracellular activation of the receptors to cellular and genetic changes are not well understood. Using primary cardiocyte cultures from neonate rat hearts, an alpha1-adrenergic regulatory sequence has been identified in the 5' flanking region of the ANF gene. This sequence, which is necessary and sufficient for transcriptional activation in response to the alpha1-specific agonist phenylephrine, interacts with novel zinc-dependent proteins which are induced by alpha1-adrenergic stimulation. Consistent with a conserved regulatory mechanism, the alpha1 response element is highly conserved between rodent, bovine 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.