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The Journal of Neuroscience, July 19, 2006, 26(29):7565-7574; doi:10.1523/JNEUROSCI.1512-06.2006

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Cellular/Molecular
Dihydropyridine Receptors and Type 1 Ryanodine Receptors Constitute the Molecular Machinery for Voltage-Induced Ca²⁺ Release in Nerve Terminals

Valérie De Crescenzo,¹ Kevin E. Fogarty,^1,3 Ronghua ZhuGe,^1,3 Richard A. Tuft,^1,3 Lawrence M. Lifshitz,^1,3 Jeffrey Carmichael,³ Karl D. Bellvé,^1,3 Stephen P. Baker,² S. Zissimopoulos,⁴ F. Anthony Lai,⁴ José R. Lemos,¹ and John V. Walsh, Jr¹

¹Department of Physiology and ²Information Services Bioinformatics Unit, University of Massachusetts Medical School, Worcester, Massachusetts 01655, ³Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and ⁴Wales Heart Research Institute, Cardiff University, Cardiff CF14 4XN, United Kingdom

Correspondence should be addressed to John V. Walsh, Department of Physiology, 55 Lake Avenue, University of Massachusetts Medical School, Worcester, MA 01655. Email: john.walsh{at}umassmed.edu

Ca²⁺ stores were studied in a preparation of freshly dissociated terminals from hypothalamic magnocellular neurons. Depolarization from a holding level of –80 mV in the absence of extracellular Ca²⁺ elicited Ca²⁺ release from intraterminal stores, a ryanodine-sensitive process designated as voltage-induced Ca²⁺ release (VICaR). The release took one of two forms: an increase in the frequency but not the quantal size of Ca²⁺ syntillas, which are brief, focal Ca²⁺ transients, or an increase in global [Ca²⁺]. The present study provides evidence that the sensors of membrane potential for VICaR are dihydropyridine receptors (DHPRs). First, over the range of –80 to –60 mV, in which there was no detectable voltage-gated inward Ca²⁺ current, syntilla frequency was increased e-fold per 8.4 mV of depolarization, a value consistent with the voltage sensitivity of DHPR-mediated VICaR in skeletal muscle. Second, VICaR was blocked by the dihydropyridine antagonist nifedipine, which immobilizes the gating charge of DHPRs but not by Cd²⁺ or FPL 64176 (methyl 2,5 dimethyl-4[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate), a non-dihydropyridine agonist specific for L-type Ca²⁺ channels, having no effect on gating charge movement. At 0 mV, the IC₅₀ for nifedipine blockade of VICaR in the form of syntillas was 214 nM in the absence of extracellular Ca²⁺. Third, type 1 ryanodine receptors, the type to which DHPRs are coupled in skeletal muscle, were detected immunohistochemically at the plasma membrane of the terminals. VICaR may constitute a new link between neuronal activity, as signaled by depolarization, and a rise in intraterminal Ca²⁺.

Key words: internal stores; presynaptic; sparks; magnocellular neurons; voltage; Ca²⁺ channels

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Received Dec. 17, 2005; revised May 25, 2006; accepted May 30, 2006.

Correspondence should be addressed to John V. Walsh, Department of Physiology, 55 Lake Avenue, University of Massachusetts Medical School, Worcester, MA 01655. Email: john.walsh{at}umassmed.edu

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