Dual regulation of atrial natriuretic factor-dependent guanylate cyclase activity by ATP

The 'second messenger' of certain atrial natriuretic factor (ANF) signals is cyclic GMP. One type of ANF receptor linked to the synthesis of cyclic GMP is a transmembrane protein which contains both the ANF-binding and guanylate cyclase activities. The consensus is that the maximal activity of this guanylate cyclase is observed in the presence of ATP. We now show that depending upon the cofactors Mg2+ or Mn2+, ATP stimulates or inhibits the ANF-dependent guanylate cyclase activity in the testicular plasma membranes: stimulation in the presence of Mg2+ and inhibition in the presence of Mn2+. With Mg2+ as cofactor neither ATP nor ANF stimulate the cyclase activity--it is only when the two are together that the enzyme is activated. Furthermore, this investigation for the first time demonstrates binding of ATP to the ANF receptor guanylate cyclase, suggesting that ATP-mediated responses could occur by direct ATP binding to the cyclase.