This lecture will summarize our studies identifying the transient receptor potential (TRP) channel TRPM4, a Ca²⁺-activated Na⁺-permeable ion channel, as a second TRP channel present in mouse vomeronsasal sensory neurons (VSNs), in addition to the diacylglycerol-sensitive and Ca²⁺ permeable TRPC2 channel. Three major results emerge from this work. First, unlike TRPC2, TRPM4 is not detectable in the microvilli of VSNs, suggesting that TRPM4 does not mediate primary chemoelectrical transduction in VSNs but rather would be ideal for a downstream, modulatory function in these neurons. Second, TRPM4 is expressed in a sex-specific manner in VSNs, in contrast to TRPC2. In the VNO of female mice, the expression of TRPM4 is synchronized to the female reproductive cycle and is upregulated specifically during proestrus and estrus, at a time when female mice are about to ovulate and become sexually active and receptive. Third, this cyclic regulation is governed by ovarian sex hormones because ovariectomy (OVX) results in permanent downregulation of TRPM4 expression, an effect that can be restored by systemic treatment of OVX mice with 17ß-estradiol but not with progesterone. On the basis of these results and other evidence, we propose that TRPM4 could be part of a novel hormone signaling cascade in the VNO, possibly required for modulating experience-dependent social behaviors through vomeronasal signaling. Our ongoing experiments are testing this central hypothesis. TRPM4 activation by hormonal signaling offers an attractive neural mechanism by which female mice could regulate the relative strength of sensory signals in their VSNs, depending on hormonal state.

Supported by Deutsche Forschungsgemeinschaft grant SFB-Transregio 152.