Polycystins (PKD2, PKD2L1, and PKD2L2) are members of the transient receptor potential family, which form ciliary ion channels. Most notably, PKD2 dysregulation in the kidney nephron cilia is associated with polycystic kidney disease, but the function of PKD2L1 in neurons is undefined. In this report, we develop animal models to track the expression and subcellular localization of PKD2L1 in the brain. We discover that PKD2L1 localizes and functions as a Ca
2+
channel in the primary cilia of hippocampal neurons that apically radiate from the soma. Loss of PKD2L1 expression ablates primary ciliary maturation and attenuates neuronal high-frequency excitability, which precipitates seizure susceptibility and autism spectrum disorder–like behavior in mice. The disproportionate impairment of interneuron excitability suggests that circuit disinhibition underlies the neurophenotypic features of these mice. Our results identify PKD2L1 channels as regulators of hippocampal excitability and the neuronal primary cilia as organelle mediators of brain electrical signaling.
Members of the polycystin family (PKD2 and PKD2L1) of transient receptor potential (TRP) channels conduct Ca2+ and depolarizing monovalent cations. Variants in PKD2 cause autosomal dominant polycystic kidney disease (ADPKD) in humans, whereas loss of PKD2L1 expression causes seizure susceptibility in mice. Understanding structural and functional regulation of these channels will provide the basis for interpreting their molecular dysregulation in disease states. However, the complete structures of polycystins are unresolved, as are the conformational changes regulating their conductive states. To provide a holistic understanding of the polycystin gating cycle, we use computational prediction tools to model missing PKD2L1 structural motifs and evaluate more than 150 mutations in an unbiased mutagenic functional screen of the entire pore module. Our results provide an energetic landscape of the polycystin pore, which enumerates gating sensitive sites and interactions required for opening, inactivation, and subsequent desensitization. These findings identify the external pore helices and specific cross‐domain interactions as critical structural regulators controlling the polycystin ion channel conductive and nonconductive states.
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