Resident Calmodulin Primes NMDA Receptors for Ca2+-Dependent Inactivation.

Abstract:

:N-methyl-d-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that flux Na+ and Ca2+ into postsynaptic neurons during synaptic transmission. The resulting intracellular Ca2+ transient is essential to physiological and pathological processes related to synaptic development, plasticity, and apoptosis. It also engages calmodulin (CaM) to reduce subsequent NMDA receptor activity in a process known as Ca2+-dependent inactivation (CDI). Here, we used whole-cell electrophysiology to measure CDI and computational modeling to dissect the sequence of events that underlies it. With these approaches, we estimate that CaM senses NMDA receptor Ca2+ influx at ∼9 nm from the channel pore. Further, when we controlled the frequency of Ca2+ influx through individual channels, we found that a kinetic model where apoCaM associates with channels before their activation best predicts the measured CDI. These results provide, to our knowledge, novel functional evidence for CaM preassociation to NMDA receptors in living cells. This particular mechanism for autoinhibitory feedback reveals strategies and challenges for Ca2+ regulation in neurons during physiological synaptic activity and disease.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Iacobucci GJ,Popescu GK

doi

10.1016/j.bpj.2017.06.035

subject

Has Abstract

pub_date

2017-11-21 00:00:00

pages

2236-2248

issue

10

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(17)30685-9

journal_volume

113

pub_type

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