Nitric oxide/ cGMP/ PKG signaling pathway activated by M1-type muscarinic acetylcholine receptor cascade inhibits Na+-activated K+ currents in Kenyon cells

The interneurons of the mushroom body, known as Kenyon cells, are essential for the long-term memory of olfactory associative learning in some insects. Some studies have reported that nitric oxide (NO) is strongly related to this long-term memory in Kenyon cells. However, the target molecules and upstream and downstream NO signaling cascades are not completely understood. Here, we analyzed the effect of the NO signaling cascade on Na⁺-activated K⁺ (K_Na) channel activity in Kenyon cells of crickets (Gryllus bimaculatus). We found that two different NO donors, S-nitrosoglutatione (GSNO) and S-nitroso-N-acetyl-DL-penicillamine (SNAP), strongly suppressed K_Na channel currents. Additionally, this inhibitory effect of GSNO on K_Na channel activity was diminished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), and KT5823, an inhibitor of protein kinase G (PKG). Next, we analyzed the role of ACh in the NO signaling cascade. ACh strongly suppressed K_Na channel currents, similar to NO donors. Furthermore, this inhibitory effect of ACh was blocked by pirenzepine, an M₁ muscarinic ACh receptor antagonist, but not by 4-DAMP and mecamylamine, an M₃ muscarinic ACh receptor antagonist and a nicotinic ACh receptor antagonist, respectively. The ACh-induced inhibition of K_Na channel currents was also diminished by PLC inhibitor, U73122, and calmodulin antagonist, W-7. Finally, we found that ACh inhibition was blocked by the NO synthase (NOS) inhibitor L-NAME. These results suggested that the ACh signaling cascade promotes NO production by activating NOS, and NO inhibits K_Na channel currents via the sGC/cGMP/PKG signaling cascade in Kenyon cells.

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