Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals

Wenyan Chen, Jeremy B. Bergsman, Xiaohua Wang, Gawain Gilkey, Carol Renée Pierpoint, Erin A. Daniel, Emmanuel M. Awumey, Philippe Dauban, Robert H. Dodd, Martial Ruat, Stephen Smith

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca2+] ([Ca2+]o) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca2+]o sensor. Here, we identify the first component in a presynaptic calcium signaling pathway. Methodology/Principal Findings: By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca2+]o than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents. Conclusions/Significance: Our experiments identify CaSR as the first component in the [Ca2+]o sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca2+]o will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca2+]o following its entry via voltage-activated Ca2+ channels. CaSR may detects such falls in [Ca2+]o and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca2+]o on release probability. CaSR is positioned to detect the dynamic changes of [Ca2+]o and provide presynaptic feedback that will alter brain excitability.

Original languageEnglish (US)
Article numbere8563
JournalPLoS One
Volume5
Issue number1
DOIs
StatePublished - Jan 5 2010

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Calcium-Sensing Receptors
Calcium Signaling
Cations
nerve tissue
Calcium
calcium
receptors
Sensors
Ion Channels
Transmitters
cations
Presynaptic Terminals
Clamping devices
Electric potential
Calcium Channels
G-Protein-Coupled Receptors
Synaptic Transmission
gamma-Aminobutyric Acid
Action Potentials
Neurotransmitter Agents

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals. / Chen, Wenyan; Bergsman, Jeremy B.; Wang, Xiaohua; Gilkey, Gawain; Pierpoint, Carol Renée; Daniel, Erin A.; Awumey, Emmanuel M.; Dauban, Philippe; Dodd, Robert H.; Ruat, Martial; Smith, Stephen.

In: PLoS One, Vol. 5, No. 1, e8563, 05.01.2010.

Research output: Contribution to journalArticle

Chen, W, Bergsman, JB, Wang, X, Gilkey, G, Pierpoint, CR, Daniel, EA, Awumey, EM, Dauban, P, Dodd, RH, Ruat, M & Smith, S 2010, 'Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals', PLoS One, vol. 5, no. 1, e8563. https://doi.org/10.1371/journal.pone.0008563
Chen, Wenyan ; Bergsman, Jeremy B. ; Wang, Xiaohua ; Gilkey, Gawain ; Pierpoint, Carol Renée ; Daniel, Erin A. ; Awumey, Emmanuel M. ; Dauban, Philippe ; Dodd, Robert H. ; Ruat, Martial ; Smith, Stephen. / Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals. In: PLoS One. 2010 ; Vol. 5, No. 1.
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AU - Daniel, Erin A.

AU - Awumey, Emmanuel M.

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