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J. Biol. Chem., Vol. 282, Issue 49, 36102-36111, December 7, 2007

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

From the Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102

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.

Received for publication, July 23, 2007 , and in revised form, September 7, 2007.

^* This work was supported by National Institutes of Health Grant AG21586 (to R. A. N.) and the State of Pennsylvania Department of Health Tobacco Formula Funds. The Drexel RNAi Resource Center is funded by grants from Drexel University and the Commonwealth of Pennsylvania under Department of Health Tobacco Formula Funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

² Present address: Nova Southeastern University, College of Osteopathic Medicine, Fort Lauderdale-Davie, FL 33328.

³ Present address: Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.

⁴ Present address: Dartmouth Medical School, Dartmouth University, Hanover, NH 03755.

⁵ Present address: Lutheran Medical Center, Brooklyn, NY 11220.

¹ To whom correspondence should be addressed: 245 N. 15th St., Philadelphia, PA 19102. E-mail: robert.nichols{at}drexel.edu.

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