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NO-sensitive guanylyl cyclase acts as the effector molecule for NO and catalyses the conversion of GTP to cGMP. The enzyme is composed of two subunits, a and b, and contains a prosthetic heme group, where NO binds. So far four subunits (a1, a2, b1, b2) have been identified and two different heterodimers (a1b1 and a2b1) have been shown to exist at the protein level. Extensive analysis of the purified isoforms (a1b1 and a2b1) did not reveal any functional differences, although the regulatory N-terminal domains of both a subunits differ considerably. To study the physiological relevance of the a1b1 and a2b1 isoforms of the NO-sensitive guanylyl cyclase, conditional knockout mice for the gene coding for the a1 or a2 subunit were generated using the Cre/loxP recombination system. It was a further aim of the present study to elucidate the relative tissue distribution of the isoforms of the NO-sensitive guanylyl cyclase in mouse. The mRNA levels of the guanylyl cyclase subunits (a1, a2, b1) were assessed using quantitative real-time PCR analysis. The highest guanylyl cyclase content was found in lung, followed by the content in brain. The a1b1 heterodimer was the predominating isoform in lung and in all other peripheral tissues tested, whereas the major occurrence of the a2b1 heterodimer was detected in brain. In particular, the hippocampus and the cerebellum were identified as the brain regions containing the highest amount of the a2b1 isoform. These results suggest the a2b1 heterodimer of NO-sensitive guanylyl cyclase as the neuronal isoform possibly being involved in some forms of synaptic plasticity.