Journal article
Mitochondria and plasma membrane Ca2+-ATPase control presynaptic Ca2+ clearance in capsaicin-sensitive rat sensory neurons
The Journal of physiology, Vol.591(10), pp.2443-2462
05/15/2013
DOI: 10.1113/jphysiol.2012.249219
PMCID: PMC3678036
PMID: 23381900
Abstract
The central processes of primary nociceptors form synaptic connections with the second-order nociceptive neurons located in the dorsal horn of the spinal cord. These synapses gate the flow of nociceptive information from the periphery to the CNS, and plasticity at these synapses contributes to centrally mediated hyperalgesia and allodynia. Although exocytosis and synaptic plasticity are controlled by Ca(2+) at the release sites, the mechanisms underlying presynaptic Ca(2+) signalling at the nociceptive synapses are not well characterized. We examined the presynaptic mechanisms regulating Ca(2+) clearance following electrical stimulation in capsaicin-sensitive nociceptors using a dorsal root ganglion (DRG)/spinal cord neuron co-culture system. Cytosolic Ca(2+) concentration ([Ca(2+)]i) recovery following electrical stimulation was well approximated by a monoexponential function with a ∼2 s. Inhibition of sarco-endoplasmic reticulum Ca(2+)-ATPase did not affect presynaptic [Ca(2+)]i recovery, and blocking plasmalemmal Na(+)/Ca(2+) exchange produced only a small reduction in the rate of [Ca(2+)]i recovery (∼12%) that was independent of intracellular K(+). However, [Ca(2+)]i recovery in presynaptic boutons strongly depended on the plasma membrane Ca(2+)-ATPase (PMCA) and mitochondria that accounted for ∼47 and 40%, respectively, of presynaptic Ca(2+) clearance. Measurements using a mitochondria-targeted Ca(2+) indicator, mtPericam, demonstrated that presynaptic mitochondria accumulated Ca(2+) in response to electrical stimulation. Quantitative analysis revealed that the mitochondrial Ca(2+) uptake is highly sensitive to presynaptic [Ca(2+)]i elevations, and occurs at [Ca(2+)]i levels as low as ∼200-300 nm. Using RT-PCR, we detected expression of several putative mitochondrial Ca(2+) transporters in DRG, such as MCU, Letm1 and NCLX. Collectively, this work identifies PMCA and mitochondria as the major regulators of presynaptic Ca(2+) signalling at the first sensory synapse, and underlines the high sensitivity of the mitochondrial Ca(2+) uniporter in neurons to cytosolic Ca(2+).
Details
- Title: Subtitle
- Mitochondria and plasma membrane Ca2+-ATPase control presynaptic Ca2+ clearance in capsaicin-sensitive rat sensory neurons
- Creators
- Leonid P Shutov - Y. M. Usachev: Department of Pharmacology, University of Iowa Carver College of Medicine, 2-340F BSB, 51 Newton Road, Iowa City, IA 52242, USAMan-Su KimPatrick R HoulihanYuliya V MedvedevaYuriy M Usachev
- Resource Type
- Journal article
- Publication Details
- The Journal of physiology, Vol.591(10), pp.2443-2462
- DOI
- 10.1113/jphysiol.2012.249219
- PMID
- 23381900
- PMCID
- PMC3678036
- NLM abbreviation
- J Physiol
- ISSN
- 0022-3751
- eISSN
- 1469-7793
- Publisher
- England
- Grant note
- T32 GM067795 / NIGMS NIH HHS R01 NS087068 / NINDS NIH HHS R01 NS072432 / NINDS NIH HHS NS072432 / NINDS NIH HHS
- Language
- English
- Date published
- 05/15/2013
- Academic Unit
- Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984040314402771
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