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The Journal of Neuroscience, May 14, 2008, 28(20):5295-5311; doi:10.1523/JNEUROSCI.4810-07.2008

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Cellular/Molecular
Mechanisms of Prolonged Presynaptic Ca²⁺ Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

Yuliya V. Medvedeva, Man-Su Kim, and Yuriy M. Usachev

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Correspondence should be addressed to Yuriy M. Usachev, Department of Pharmacology, University of Iowa Carver College of Medicine, 2-250 BSB, 51 Newton Road, Iowa City, IA 52242. Email: yuriy-usachev{at}uiowa.edu

Transient receptor potential vanilloid receptor 1 (TRPV1)-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca²⁺ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N-arachidonoyl-dopamine induces a prolonged elevation of presynaptic [Ca²⁺]_i and a concomitant enhancement of glutamate release at sensory synapses. Initiation of this response required Ca²⁺ entry, primarily via TRPV1. The sustained phase of the response was independent of extracellular Ca²⁺ and was prevented by inhibitors of mitochondrial Ca²⁺ uptake and release mechanisms. Measurements using a mitochondria-targeted Ca²⁺ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca²⁺ elevation in presynaptic mitochondria. The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca²⁺ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons. These data suggest that mitochondria control vanilloid-induced neurotransmission by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.

Key words: TRPV1; capsaicin; NADA; calcium; mitochondria; DRG neurons

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Received Oct. 23, 2007; revised March 7, 2008; accepted April 2, 2008.

Correspondence should be addressed to Yuriy M. Usachev, Department of Pharmacology, University of Iowa Carver College of Medicine, 2-250 BSB, 51 Newton Road, Iowa City, IA 52242. Email: yuriy-usachev{at}uiowa.edu

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