The beta 2 subunit inhibits stimulation of the alpha 1/beta 1 form of soluble guanylyl cyclase by nitric oxide - Potential relevance to regulation of blood pressure

Cytosolic guanylyl cyclases (GTP pyrophosphate-lyase [cyclizing; EC 4.6.1.2]), primary receptors for nitric oxide (NO) generated by NO synthases, are obligate heterodimers consisting of an alpha and a beta subunit, The alpha 1/beta 1 form of guanylyl cyclase has the greatest activity and is considered the universal form, An isomer of the beta 1 subunit, i.e., beta 2, has been detected in the liver and kidney, however, its role is not known, In this study, we investigated the function of beta 2, Immunoprecipitation experiments showed that the beta 2 subunit forms a heterodimer with the alpha 1 subunit, NO-stimulated cGMP formation in COS 7 cells cotransfected with the alpha 1 and beta 2 subunits was similar to 1/3 Of that when alpha 1 and beta 1 subunits were cotransfected. The beta 2 subunit inhibited NO-stimulated activity of the alpha 1/beta 1 form of guanylyl cyclase and NO-stimulated cGMP formation in cultured smooth muscle cells, Our results provide the first evidence that the beta 2 subunit can regulate NO sensitivity of the alpha 1/beta 1 form of guanylyl cyclase, Northern analysis for guanylyl cyclase subunits was performed on RNA from kidneys of Dahl salt-sensitive rats, which have been shown to have decreased renal sensitivity to NO, Compared to the Dahl salt-resistant rat, message for beta 2 was increased, beta 1 was decreased, and alpha 1 was unchanged. These results suggest a molecular basis for decreased renal guanylyl cyclase activity, i.e., an increase in the alpha 1/beta 2 heterodimer, and decrease in the alpha 1/beta 1 heterodimer.