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The Journal of Neuroscience, November 12, 2008, 28(46):12062-12070; doi:10.1523/JNEUROSCI.4134-08.2008

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Cellular/Molecular
Calcium-Sensing Receptor Activation Depresses Synaptic Transmission

Cecilia G. Phillips, Mark T. Harnett, Wenyan Chen, and Stephen M. Smith

Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, Oregon 97239

Correspondence should be addressed to Dr. Stephen M. Smith, Division of Pulmonary & Critical Care Medicine, 3181, SW Sam Jackson Park Road, UHN-67, Oregon Health & Science University, Portland, OR 97239. Email: smisteph{at}ohsu.edu

At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca]o) and thus may impair neurotransmission. Increases in [Ca]o activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits nonselective cation channels at the majority of cortical nerve terminals. This pathway may modulate synaptic transmission by attenuating the impact of decreases in [Ca]o on synaptic transmission. Using patch-clamp recording from isolated cortical terminals, cortical neuronal pairs and isolated neuronal soma we examined the modulation of synaptic transmission by CaSR. EPSCs were increased on average by 88% in reduced affinity CaSR-mutant (CaSR–/–) neurons compared with wild-type. Variance-mean analysis indicates that the enhanced synaptic transmission was due largely to an increase in average probability of release (0.27 vs 0.46 for wild-type vs CaSR–/– pairs) with little change in quantal size (23 ± 4 pA vs 22 ± 4 pA) or number of release sites (11 vs 13). In addition, the CaSR agonist spermidine reduced synaptic transmission and increased paired-pulse depression at physiological [Ca]o. Spermidine did not affect quantal size, consistent with a presynaptic mechanism of action, nor did it affect voltage-activated Ca channel currents. In summary, reduced CaSR function enhanced synaptic transmission and CaSR stimulation had the opposite effect. Thus CaSR provides a mechanism that may compensate for the fall in release probability that accompanies decreases in [Ca]o.

Key words: calcium; GPCR; depression; synaptic plasticity; synaptic transmission; synaptic vesicle release; synaptosome; extracellular; receptor

Received Aug. 29, 2008; revised Sept. 30, 2008; accepted Oct. 5, 2008.

Correspondence should be addressed to Dr. Stephen M. Smith, Division of Pulmonary & Critical Care Medicine, 3181, SW Sam Jackson Park Road, UHN-67, Oregon Health & Science University, Portland, OR 97239. Email: smisteph{at}ohsu.edu






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