Influx-Operated Ca²⁺ Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli

The polycystic TRP subfamily member PKD2-L1, in complex with PKD1-L3, is involved in physiological responses to diverse stimuli. A major challenge to understanding whether and how PKD2-L1/PKD1-L3 acts as a bona fide molecular transducer is that recombinant channels usually respond with small or undetectable currents. Here, we discover a type of Ca²⁺ influx-operated Ca²⁺ entry (ICE) that generates pronounced Ca²⁺ spikes. Triggered by rapid onset/offset of Ca²⁺, voltage, or acid stimuli, Ca²⁺-dependent activation amplifies a small Ca²⁺ influx via the channel. Ca²⁺ concurrently drives a self-limiting negative feedback (Ca²⁺-dependent inactivation) that is regulated by the Ca²⁺-binding EF hands of PKD2-L1. Our results suggest a biphasic ICE with opposite Ca²⁺ feedback regulation that facilitates sensory responses to multimodal transient stimuli. We suggest that such a mechanism may also occur for other sensory modalities and other Ca²⁺ channels.