Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

Abstract

NMDA receptors are glutamate-sensitive ion channel receptors that mediate excitatory synaptic transmission and are widely implicated in synaptic plasticity and integration of synaptic activity in the CNS. This is in part attributable to the high calcium permeability of the ion channel, which allows receptor activation to influence the intracellular calcium concentration and also the slow time course of NMDA receptor-mediated synaptic currents. NMDA receptor activity is also regulated by the intracellular calcium concentration through activation of various calcium-dependent proteins, including calmodulin, calcineurin, protein kinase C, and ␣-actinin-2. Here, we have shown that calmodulin reduces the duration of native NMDA receptor single-channel openings from 3.5 Ϯ 0.6 msec to 1.71 Ϯ 0.2 msec in agreement with previous studies on recombinant NMDA receptors (Ehlers et al., 1996). NMDA receptor single-channel amplitudes and shut times were not affected.However, calmodulin reduced the duration of groups of channel openings called superclusters, which determine the slow time course of synaptic currents, from 121 Ϯ 25.4 msec to 60.4 Ϯ 11.6 msec. In addition, total open time, number of channel openings, and charge transfer per supercluster were all reduced by calmodulin. A 68% decrease in charge transfer per supercluster suggests that calmodulin activation will significantly reduce calcium influx during synaptic transmission. These results suggest that calmodulin-dependent inhibition of NMDA receptors will reduce the amplitude and time course of excitatory synaptic currents and thus affect synaptic plasticity and integration of synaptic activity in the CNS.

Differential Calcium-Dependent Modulation of NMDA Currents in CA1 and CA3 Hippocampal Pyramidal Cells

“…In contrast, the processes underlying the Ca 2ϩ -dependent inactivation of NMDA receptors are less understood. A number of Ca 2ϩ -dependent proteins, including calmodulin, calcineurin, PKC, and ␣-actinin-2, are implicated in the regulation of NMDAR function (Rycroft and Gibb, 2002). Of particular interest in light of our data are the recent reports that striatal-enriched protein tyrosine phosphatase (STEP), which is also expressed in hippocampus, is activated by calcineurin as a result of Ca 2ϩ entry through NMDARs (Paul et al, 2003).…”

C-terminal Domains of N-Methyl-d-aspartic Acid Receptor Modulate Unitary Channel Conductance and Gating

“…Previous reports demonstrated that N1 CTDs mediate Ca 2ϩ -dependent modulation of NR kinetics. ␣-Actinin and/or calmodulin modulate single-channel gating of NRs via binding sites located within the N1 CTD (30,57,58). These proteinprotein interactions, as well as the phosphorylation status of N1 CTD residues, influence Ca 2ϩ -dependent inactivation of NR macroscopic currents (19,20).…”

Organization and Regulation of Small Conductance Ca2+-activated K+Channel Multiprotein Complexes

“…For SK channels, CaM mediates Ca 2ϩ gating, increasing activity, whereas CK2 phosphorylation of SK2-associated CaM reduces channel activity. For NMDA receptors, CaM mediates Ca 2ϩ -induced inactivation (Ehlers et al, 1996;Krupp et al, 1999;Rycroft and Gibb, 2002), whereas CK2 phosphorylation enhances activity (Lieberman and Mody, 1999). Therefore, the activation of CK2 may additively increase the NMDA component of EPSPs, by directly increasing NMDA receptor activity and decreasing the SK-mediated repolarization that favors reblock of NMDA receptors by external Mg 2ϩ ions.…”