Ca2+ influx-independent synaptic potentiation mediated by mitochondrial Na+-Ca2+ exchanger and protein kinase C

doi:10.1083/jcb.200307027

Published 10 November 2003. doi:10.1083/jcb.200307027

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© The Rockefeller University Press, 0021-9525/2003/11/511 $8.00
The Journal of Cell Biology, Volume 163, Number 3, 511-523

Article

Ca²⁺ influx–independent synaptic potentiation mediated by mitochondrial Na⁺-Ca²⁺ exchanger and protein kinase C

Feng Yang¹, Xiang-ping He¹, James Russell² and Bai Lu¹

¹ Section on Neural Development and Plasticity, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
² Section on Cell Biology and Signal Transduction, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Bai Lu, Section on Neural Development and Plasticity, NICHD, NIH, Building 49, Rm. 6A80, 49 Convent Dr., Bethesda, MD 20892-4480. Tel.: (301) 435-2970. Fax: (301) 496-1777. email: bailu{at}mail.nih.gov

Activity-dependent modulation of synaptic transmission is anessential mechanism underlying many brain functions. Here wereport an unusual form of synaptic modulation that depends onNa⁺ influx and mitochondrial Na⁺-Ca²⁺ exchanger, but not onCa²⁺ influx. In Ca²⁺-free medium, tetanic stimulation of Xenopusmotoneurons induced a striking potentiation of transmitter releaseat neuromuscular synapses. Inhibition of either Na⁺ influx orthe rise of Ca²⁺ concentrations ([Ca²⁺]_i) at nerve terminalsprevented the tetanus-induced synaptic potentiation (TISP).Blockade of Ca²⁺ release from mitochondrial Na⁺-Ca²⁺ exchanger,but not from ER Ca²⁺ stores, also inhibited TISP. Tetanic stimulationin Ca²⁺-free medium elicited an increase in [Ca²⁺]_i, which wasprevented by inhibition of Na⁺ influx or mitochondrial Ca²⁺release. Inhibition of PKC blocked the TISP as well as mitochondrialCa²⁺ release. These results reveal a novel form of synapticplasticity and suggest a role of PKC in mitochondrial Ca²⁺ releaseduring synaptic transmission.

Key Words: synaptic plasticity; neuromuscular junction; mitochondria; Na⁺-Ca²⁺ exchanger; Ca²⁺ influx

Abbreviations used in this paper: CaMKII, Ca²⁺/calmodulin-dependentkinase II; CGP, CGP37157; CheT, chelerythrine; DRG, dorsal rootganglion; ESC, evoked synaptic current; FCCP, carbonyl cyanide4-(trifluoromethoxy) phenyl hydrazone; GF, GF 1092303X; IP3,inositol 1,4,5-trisphosphate; LTP, long-term potentiation; NMDG,N-methyl-D-glucamine; NMJ, neuromuscular junction; PTP, post-tetanicpotentiation; SSC, spontaneous synaptic current; TISP, tetanus-inducedsynaptic potentiation; TTX, tetrodotoxin; XeC, XestosponginC.

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