Modal Bifurcation of Cav1.3 Signaling in Cortical Neurons

L-type Ca2+ channels, emerging as one of the central signaling hubs in healthy and diseased neurons, play prominent roles in diverse essential processes. However, it still remains largely as a puzzle how the same channel could simultaneously fulfill opposed tasks of signaling in neurons. Here we report that CaV1.3 channels are bifurcated into subpopulations with two distinct modes of signaling: n-mode signaling and p-mode signaling. This modal bifurcation is first demonstrated by genetically-encoded Ca2+ channel tuners (GECTs) of iCaMp and eCaMp, bioengineered to perturb autonomous competition between calmodulin and distal carboxyl tail of CaV1.3 channel. Channels driven into p-mode by eCaMp tend to produce “sharp and large” Ca2+ influx, which is kinetically distinguished from “blunt and small” Ca2+ influx via n-mode channels by iCaMp. Moreover, in cultured cortical neurons, modal bifurcation of CaV1.3 channels provides a pair of homeostatic opponents leading to constructive and destructive signaling events, eventually to morphological changes. In these neurons, kinase and phosphatase are preferentially activated by respective p-mode or n-mode channels and signals. Correspondingly, CaV1.3 signaling complex switches between its configurations to facilitate such signaling preference. Finally, the capabilities of GECTs, especially those of eCaMp in promoting p-mode channels and signals, highlight a new strategy to modulate L-type Ca2+ channels, as potential therapeutics for disorders with certain malfunctioned channels and/or dys-regulated homeostasis.