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

•PKD2-L1/PKD1-L3 channel Ca2+ influx drives both positive and negative feedback•Ca2+ spikes are inducible when the balance of this feedback is well tuned•Sensory responses to stimuli with rapid onset/offset are facilitated by Ca2+ spikes•Ca2+-binding EF hands of PKD2-L1 regulate Ca2+ feedback and Ca2+ spikes

SummaryThe 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.

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