Hyperpolarization induced by Homer1a/Vesl1S injection is independent on IP₃-assisted CICR in neocortex pyramidal cells

Abstract

We reported a novel feedback regulation of pyramidal cell firing in the rat visual cortex, in which spike-induced Ca²⁺ influx triggers Ca²⁺ release from IP₃ receptors (IP₃Rs) sensitized by a prior increase in IP₃ (IP₃-assisted CICR), thereby activating SK channels in an enhanced fashion (Yamamoto et al., 2002; Yamada et al., 2004). Activation of group I metabotropic glutamate receptors (mGluRs) was shown to suffice to provide the requisite IP₃. Homer/Vesl proteins, which bind both IP₃Rs and mGluRs, may well be involved in this feedback. To probe this possible Homer/Vesl involvement, we have studied whether an activity-dependently inducible member of Homers/Vesls, Homer1a/Vesl1S, affects pyramidal cell excitability. Injection of Homer1a/Vesl1S protein through whole-cell pipettes elicited hyperpolarization by 5-10 mV. This hyperpolarization was prevented by co-applying either the mGluR antagonist MPEP, PLC inhibitor U-73122, IP₃R blocker heparin, Ca²⁺ indicator/chelator fura-2, or BK class Ca²⁺-activated K⁺ channel antagonist charybdotoxin, but not by the SK channel blocker dequalinium. These findings suggest that activation of mGluR by Homer1a/Vesl1S produces IP₃, then causes inositol-induced Ca²⁺ release and a consequent BK channel opening, and finally leads to hyperpolarization. To our surprise, neither was this membrane stabilization triggered by spike firing nor achieved by SK channel opening, therefore depending unlikely on IP₃-assisted CICR. [Jpn J Physiol 54 Suppl:S137 (2004)]