A Constitutive, Transient Receptor Potential-like Ca2+ Influx Pathway in Presynaptic Nerve Endings Independent of Voltage-gated Ca2+ Channels and Na+/Ca2+ Exchange*

Calcium levels in the presynaptic nerve terminal are altered by several pathways, including voltage-gated Ca2+ channels, the Na+/Ca2+ exchanger, Ca2+-ATPase, and the mitochondria. The influx pathway for homeostatic control of [Ca2+]i in the nerve terminal has been unclear. One approach to detecting the pathway that maintains internal Ca2+ is to test for activation of Ca2+ influx following Ca2+ depletion. Here, we demonstrate that a constitutive influx pathway for Ca2+ exists in presynaptic terminals to maintain internal Ca2+ independent of voltage-gated Ca2+ channels and Na+/Ca2+ exchange, as measured in intact isolated nerve endings from mouse cortex and in intact varicosities in a neuronal cell line using fluorescence spectroscopy and confocal imaging. The Mg2+ and lanthanide sensitivity of the influx pathway, in addition to its pharmacological and short hairpin RNA sensitivity, and the results of immunostaining for transient receptor potential (TRP) channels indicate the involvement of TRPC channels, possibly TRPC5 and TRPC1. This constitutive Ca2+ influx pathway likely serves to maintain synaptic function under widely varying levels of synaptic activity.

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