We present structures of mouse TRPV3 in temperature-dependent open, closed and intermediate states that suggest two-step activation of TRPV3 by heat. During the strongly temperaturedependent first step, sensitization, the channel pore remains closed while S6 helices undergoe αto-π transitions. During the weakly temperature-dependent second step, channel opening, tight association of the S1-S4 and pore domains is stabilized by changes in the C-terminal and linker domains.Temperature perception is mediated by temperature-sensitive transient receptor potential (TRP) channels, thermo-TRPs, that exhibit unusually high temperature coefficient (Q 10 ) values compared to non-temperature sensitive ion channels [1][2][3][4] . Four members of the vanilloid subfamily TRP channels are thermo-TRPs: TRPV1 and TRPV2 are activated by Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Zn2+, Mg2+, and Ca2+are essential minerals required for a plethora of metabolic processes and signaling pathways. Different categories of cation-selective channels and transporters are therefore required to tightly control the cellular levels of individual metals in a cell-specific manner. However, the mechanisms responsible for the organismal balance of these essential minerals are poorly understood. Herein, we identify a central and indispensable role of the channel-kinase TRPM7 for organismal mineral homeostasis. The function of TRPM7 was assessed by single-channel analysis of TRPM7, phenotyping of TRPM7-deficient cells in conjunction with metabolic profiling of mice carrying kidney- and intestine-restricted null mutations inTrpm7and animals with a global “kinase-dead” point mutation in the gene. The TRPM7 channel reconstituted in lipid bilayers displayed a similar permeability to Zn2+and Mg2+. Consistently, we found that endogenous TRPM7 regulates the total content of Zn2+and Mg2+in cultured cells. Unexpectedly, genetic inactivation of intestinal rather than kidney TRPM7 caused profound deficiencies specifically of Zn2+, Mg2+, and Ca2+at the organismal level, a scenario incompatible with early postnatal growth and survival. In contrast, global ablation of TRPM7 kinase activity did not affect mineral homeostasis, reinforcing the importance of the channel activity of TRPM7. Finally, dietary Zn2+and Mg2+fortifications significantly extended the survival of offspring lacking intestinal TRPM7. Hence, the organismal balance of divalent cations critically relies on one common gatekeeper, the intestinal TRPM7 channel.

SUMMARY Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor, TRPV1, is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, irrespective of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble RTX/DkTx. Together our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.