Hippocampal GABAergic synapses possess the molecular machinery for retrograde nitric oxide signaling.
The diffusible messenger nitric oxide (NO) acts in the brain largely through activation of soluble guanylyl cyclase (sGC), a heterodimer comprising alpha and beta subunits. We used immunohistochemistry to study the distribution of both sGC subunits in the brain of adult rats. alpha and beta subunits gave similar widespread staining throughout the CNS, which was strongest in neostriatum, olfactory tubercle, and supraoptic nucleus. Double-labeling experiments showed striking cellular colocalization in most brain regions, suggesting that the two subunits may be organized into enzymatically active alpha/beta heteromers. Mismatches were observed in cerebellar cortex: Purkinje cells and Bergmann glia were positive for both subunits, whereas granule cells and interneurons in the molecular layer were strongly immunopositive for beta but only weakly stained for the alpha subunit. By using multiple labeling, we compared the localization of sGC with neuronal nitric oxide synthase (NOS-I, the NO-producing enzyme in neurons). In forebrain, the distribution of sGC and NOS-I was complementary, with only occasional colocalization. In contrast, cellular colocalization was common in midbrain and cerebellum. These data support a widespread role for the NO/sGC/cGMP pathway in the CNS and suggest that, in addition to its role as paracrine messenger, NO may also be an intracellular autocrine agent.