Pituitary adenylate cyclase activating polypeptide reduces expression of Kv1.4 and Kv4.2 subunits underlying A-type K+ current in adult mouse olfactory neuroepithelia

A-type K+ currents (IA) in olfactory receptor neurons have been characterized electrophysiologically but the molecular identities of the underlying channel subunits have not been determined. Using RT-PCR, immunoblot and immunohistochemistry, we found that the two candidate channel families underlying IA, shaker and shal, are expressed in olfactory epithelia of Swiss Webster mice. Specifically, Kv1.4, the only IA candidate from the shaker family, and Kv4.2 and Kv4.3 from the shal family were expressed, but Kv4.1 mRNA was not amplified from the olfactory epithelia. Immunoblot and immunohistochemical studies confirmed the existence of Kv1.4 and Kv4.2/3 subunits. Furthermore, quantitative RT-PCR showed that pituitary adenylate cyclase activating polypeptide (PACAP) reduced the expression of Kv1.4 and Kv4.2 but did not reduce the already low expression of Kv4.3. The PACAP-induced reduction of Kv4.1 and Kv4.2 expression was completely blocked by inhibiting the phospholipase C (PLC) pathway but was still significantly downregulated by PACAP when the cyclic AMP pathway was inhibited. In addition, downstream of the PLC pathway, calcium mediated the reduction of both Kv1.4 and Kv4.2 expression and IA current density. Phosphokinase C (PKC) activation did not affect Kv1.4 and Kv4.2 mRNA expression, even though PKC reduced IA current density. Together with our previous studies, our data suggest that A-type K+ currents in olfactory receptor neurons are composed of multiple K+ channel subunits, among which Kv1.4 and Kv4.2 are subject to transcriptional modulation by PACAP. We also found that PACAP predominately uses a PLC-calcium pathway to modulate Kv4.1 and Kv4.2 expression. Modulation of A-type K+ current expression may contribute to the previously observed neuroprotective effects of PACAP on olfactory receptor neurons.