NO-sensitive guanylyl cyclase (GC) acts as the effector molecule for NO and therefore plays a key role in the NO/cGMP signalling cascade. Besides the long known GC isoform (alpha(1)beta(1)), another heterodimer (alpha(2)beta(1)) has recently been identified to be associated with PSD-95 in brain.Here, we report on the tissue distribution of all known guanylyl cyclase subunits to elucidate the isoform content in different tissues of the mouse. The guanylyl cyclase subunit levels were assessed with quantitative real-time PCR, and the most important results were verified in Western blots. We demonstrate the major occurrence of the alpha(2)beta(1) heterodimer in brain, find a significant amount in lung and lower amounts in all other tissues tested. In brain, the levels of the alpha(2)beta(1) and alpha(1)beta(1) isoforms were comparable; in all other tissues, the alpha(1)beta(1) heterodimer was the predominating isoform. The highest guanylyl cyclase content was found in lung; here the GC amounted to approximately twice as much as in brain. In sum, the major occurrence of the alpha(2)beta(1) heterodimer suggests a special role in synaptic transmission; whether this isoform outside the brain also occurs in neuronal networks has to be addressed in future studies.