THE BETA(2)-ADRENERGIC RECEPTOR INTERACTS WITH THE NA+ H+-EXCHANGER REGULATORY FACTOR TO CONTROL NA+/H+ EXCHANGE/

Stimulation of beta(2)-adrenergic receptors on the cell surface by adr enaline or noradrenaline leads to alterations in the metabolism, excit ability, differentiation and growth of many cell types. These effects have traditionally been thought to be mediated exclusively by receptor activation of intracellular G proteins(1). However, certain physiolog ical effects of beta(2)-adrenergic receptor stimulation, notably the r egulation of cellular pH by modulation of Na+/H+ exchanger (NHE) funct ion, do not seem to be entirely dependent on G-protein activation(2-7) . We report here a direct agonist-promoted association of the beta(2)- adrenergic receptor with the Na+/H+ exchanger regulatory factor (NHERF ), a protein that regulates the activity of the Na+/H+ exchanger type 3 (NHE3)(8). NHERF binds to the beta(2)-adrenergic receptor by means o f a PDZ-domain-mediated interaction with the last few residues of the carboxy-terminal cytoplasmic domain of the receptor. Mutation of the f inal residue of the beta(2)-adrenergic receptor from leucine to alanin e abolishes the receptor's interaction with NHERF and also markedly al ters beta(2)-adrenergic receptor regulation of NHE3 in cells without a ltering receptor-mediated activation of adenylyl cyclase. Our findings indicate that agonist-defendent beta(2)-adrenergic receptor binding o f NHERF plays a role in beta(2)-adrenergic receptor-mediated regulatio n of Na+/H+ exchange.