Olfaction, a chemosensory modality, plays a pivotal role in the orientation and behavior of invertebrates. The central olfactory processing unit in terrestrial stylomatophoran snails is the procerebrum, which contains NO synthesizing interneurons, whose oscillatory currents are believed to be the base of odor evoked memory formation. Nevertheless, in this model the up-and downstream events of molecular cascades that trigger and follow NO release, respectively, have not been studied. Immunocytochemistry and flow cytometry studies performed on procerebral neural perikarya isolated from the snail Helix pomatia revealed cell populations with discrete DAF-2 fluorescence, indicating the release of different amounts of NO. Glutamate increased the intensity of DAF-2 fluorescence, and the number of DAF-2 positive non-bursting interneurons, through a mechanism likely to involve an NMDA-like receptor. Similarly to glutamate, NO activation induced an increase in intracellular cGMP levels through activation of soluble guanylyl cyclase. Immunohistochemical localization of proteins possessing the phosphorylated target sequence of AGC family kinases (RXXS/T-P), among them protein kinase A (RRXS/T-P), showed striking similarities to the distribution of NOS/cGMP. Activators of cyclic nucleotide synthesis increased the AGC-kinase-dependent phosphorylation of discrete proteins with 28, 45, and 55 kDa mw. Importantly, exposure of snails to an attractive odorant induced hyperphosphorylation of the 28 kDa protein, and increased levels of cGMP synthesis. Protein S-nitrosylation and intercellular activation of protein kinase G were also suggested as Abbreviations: 5-HT, 5-hydroxytryptamine or serotonin; ACh, acetylcholine; AGC-S-P, phosphorylated substrate of the AGC-family protein kinase; Akt, protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; APV, (2R)-amino-5-phosphonovaleric acid; B cell, large bursting neuron in the procerebrum; β-NADP, β-nicotinamide adenine dinucleotide; β-NADPH, β-nicotinamide adenine dinucleotide 2′-phosphate; BSA, bovine serum albumin; cAMP, 3′,5′-cyclic adenosine monophosphate;