Abstract
Group I metabotropic glutamate receptors (group I mGluRs; mGluR1 and mGluR5) exert diverse effects on neuronal and synaptic functions, many of which are regulated by intracellular Ca2+. In this study, we characterized the cellular mechanisms underlying Ca2+ mobilization induced by (RS)-3,5-dihydroxyphenylglycine (DHPG; a specific group I mGluR agonist) in the somata of acutely dissociated rat hippocampal neurons using microfluorometry. We found that DHPG activates mGluR5 to mobilize intracellular Ca2+ from ryanodine-sensitive stores via cyclic adenosine diphosphate ribose (cADPR), while the PLC/IP3 signaling pathway was not involved in Ca2+ mobilization. The application of glutamate, which depolarized the membrane potential by 28.5±4.9 mV (n = 4), led to transient Ca2+ mobilization by mGluR5 and Ca2+ influx through L-type Ca2+ channels. We found no evidence that mGluR5-mediated Ca2+ release and Ca2+ influx through L-type Ca2+ channels interact to generate supralinear Ca2+ transients. Our study provides novel insights into the mechanisms of intracellular Ca2+ mobilization by mGluR5 in the somata of hippocampal neurons.
Highlights
The group I metabotropic glutamate receptors, which include mGluR1 and mGluR5, play important roles in regulating intrinsic excitability and synaptic plasticity [1,2,3]
DHPG-induced Ca2+ transients were not affected by the removal of external Ca2+ or the inhibition of receptor-operated Ca2+ entry by SKF96365 (10 mM), but they were markedly suppressed when cells were pretreated with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor thapsigargin (2 mM) for 5 min, indicating that DHPG mobilizes Ca2+ from its intracellular stores (Figure 1C–1E)
Our results indicate that the cyclic adenosine diphosphate ribose (cADPR) signaling pathways are responsible for the mGluR5-induced Ca2+ mobilization from ryanodine-sensitive stores
Summary
The group I metabotropic glutamate receptors (mGluRs), which include mGluR1 and mGluR5, play important roles in regulating intrinsic excitability and synaptic plasticity [1,2,3]. Enhancement of neuronal excitability [4,5,6] and long-term depression mediated by mGluR (mGluR-LTD) [7] were shown to be blocked by intracellular dialysis of BAPTA, and the involvement of Ca2+-dependent proteins such as PICK1 and NCS-1 in mGluR-LTD has recently been demonstrated [8,9,10]. It is well known that group I mGluRs mobilize Ca2+ from intracellular stores in hippocampal neurons [13,14]. As group I mGluRs are coupled to Gq proteins [15,16], Ca2+ mobilization may involve the phospholipase C (PLC)/inositol-3-triphosphate (IP3) signaling pathways [1]. Studies in midbrain dopaminergic neurons demonstrated that intracellular Ca2+
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