Non-canonical, ligand-independent basal mGluR1 signaling tunes Kv1.2 surface expression through PKA

Abstract Voltage gated potassium channels are major determinants of excitability of Purkinje cell (PC) neurons in the cerebellum. We have previously shown that in the cerebellum, activation of mGluR1 with agonist DHPG leads to reduced surface expression of Kv1.2 and that Kv1.2 co-immunoprecipitates with PKC-γ and CaMKII which are known interactors of mGluR1. However, mGluR1 can also signal independently of agonist through a constitutively active, protein kinase A-dependent pathway. Here we show that in HEK293 cells, co-expression of mGluR1 increases the surface expression levels of Kv1.2. This effect occurs in absence of mGluR1 agonists and in the presence of an mGluR1 inhibitor. Co-expression of known downstream effectors of the agonist driven mGluR1 pathway, including PKC-γ and CaMKII, had no effect on Kv1.2 surface expression or on the ability of mGluR1 agonist to modulate that expression. In contrast, the inverse agonist BAY 36-7620 significantly reduced the mGluR1 effect on Kv1.2 surface expression, as did pharmacological inhibition of PKA with KT5720.