Regulation of the atrial natriuretic peptide receptor by heat shock protein 90 complexes

Heat shock protein 90 (hsp90) is a chaperone required for the proper foldin g and trafficking of many proteins involved in signal transduction. We test ed whether hsp90 plays a role as a chaperone for GC-A, the membrane guanyla te cyclase that acts as a receptor for atrial natriuretic peptide (ANP). Wh en cultured cells expressing recombinant GC-A were treated with geldanamyci n, an inhibitor of hsp90 function, the ANP-stimulated production of cyclic GMP was inhibited. This suggested that hsp90 was required for GC-A processi ng and/or stability. A physical association between hsp90 and GC-A was demo nstrated in coimmunoprecipitation experiments. Treatment with geldanamycin disrupted this association and led to the accumulation of complexes contain ing GC-A and heat shock protein 70 (hsp70). Protein folding pathways involv ing hsp70 and hsp90 include several pathway-specific co-chaperones. Complex es between GC-A and hsp90 contained the co-chaperone p50(cdc37), typically found associated with protein. kinase hsp(90) heterocomplexes, GC-A immunop recipitates did not contain detectable amounts of Hop, FKBP51, FKBP52, PP5, or p23, all co-chaperones found in hsp90 complexes with other signaling pr oteins. The association of hsp90 and p50(cdc37) with GC-A was dependent on the kinase homology domain of this receptor but not on its ANP-binding, tra nsmembrane, or guanylate cyclase domains. The data suggest that GC-A is reg ulated by hsp90 complexes similar to those involved in the maturation of pr otein kinases.