BAY 41-2272 activates two isoforms of nitric oxide-sensitive guanylyl cyclase.

Soluble guanylyl cyclase is an important target for endogenous nitric oxide and the guanylyl cyclase modulator, YC-1. Recently BAY 41-2272 was identified as a similar but more potent and more specific substance. While YC-1 also acts as non-specific phosphodiesterase inhibitor, BAY 41-2272 is devoid of an effect on phosphodiesterases. BAY 41-2272 has so far only been tested on the α1/β1 heterodimeric isoform of soluble guanylyl cyclase and its binding site has been mapped to a region in the α1 subunit amino-terminal sequence. Although this region is poorly conserved in the α2 subunit, we show in the current study that the α2/β1 heterodimeric enzyme isoform is activated by BAY 41–2272. Deletion analysis of the α2 subunit and co-expression with the β1 subunit in the baculovirus/Sf9 system is consistent with the amino-terminal amino acids 104 to 401 of the α2 subunit as binding site for BAY 41-2272.