Ca2+ entry through NaV channels generates submillisecond axonal Ca2+ signaling
Naomi AK Hanemaaijer, Marko Popović, Xante Wilders, Sara Grasman, Oriol Pavón Arocas, Maarten H. P. Kole
Abstract
Calcium ions (Ca 2+ ) are essential for many cellular signaling mechanisms and enter the cytosol mostly through voltage-gated calcium channels. Here, using high-speed Ca 2+ imaging up to 20 kHz in the rat layer five pyramidal neuron axon we found that activity-dependent intracellular calcium concentration ([Ca 2+ ] i ) in the axonal initial segment was only partially dependent on voltage-gated calcium channels. Instead, [Ca 2+ ] i changes were sensitive to the specific voltage-gated sodium (Na V ) channel blocker tetrodotoxin. Consistent with the conjecture that Ca 2+ enters through the Na V channel pore, the optically resolved I Ca in the axon initial segment overlapped with the activation kinetics of Na V channels and heterologous expression of Na V 1.2 in HEK-293 cells revealed a tetrodotoxin-sensitive [Ca 2+ ] i rise. Finally, computational simulations predicted that axonal [Ca 2+ ] i transients reflect a 0.4% Ca 2+ conductivity of Na V channels. The findings indicate that Ca 2+ permeation through Na V channels provides a submillisecond rapid entry route in Na V -enriched domains of mammalian axons.