The transient receptor potential melastatin 3 (TRPM3) channel is a calcium-permeable ion channel implicated in synaptic neurotransmission and sensory signaling in the central nervous system. Accordingly, the gain-of-function mutations in TRPM3, such as those of N1116D and S1123P, have been associated with neurodevelopmental disorders, including intellectual disability and epileptic seizures, by promoting sustained channel activation. While previous cryo-EM studies have elucidated TRPM3 gating and inhibition mechanisms, the structural basis for inactivation remains elusive. Here, we present high-resolution cryo-EM structures of TRPM3 in apo state and in a calmodulin-bound inactivated state. These structures reveal a previously uncharacterized mode of calmodulin (CaM)-mediated gating modulation and the involvement of specific lipid interactions in stabilizing the inactivated state. Our findings provide new molecular insights into how disease-associated mutations impair the normal inactivation, leading to channel hyperactivity. This study deepens our understanding of TRPM3 regulation and identifies potential structural targets for therapeutic intervention in TRPM3-linked neurological disorders.
Appu K. Singh (Sun,) studied this question.