Fractional contribution of calcium to the cation current through glutamate receptor channels

doi:10.1016/0896-6273(93)90277-X

Neuron

Volume 11, Issue 1, July 1993, Pages 133-143

https://doi.org/10.1016/0896-6273(93)90277-X Get rights and content

Abstract

The Ca²⁺ fraction of the ion current flowing through glutamatergic NMDA and AMPA/kainate receptor channels was determined in forebrain neurons of the medial septum. The neurons were overloaded with the Ca²⁺ indicator dye fura-2 (1 mM) via the recording patch pipettes. This approach allowed the direct determination of the Ca²⁺ influx from changes in the Ca²⁺-sensitive fura-2 fluorescence. We found that, at negative membrane potentials and at an extracellular free Ca²⁺ concentration of 1.6 mM, the Ca²⁺ fraction of the current through the NMDA receptor channels is only 6.8%, about 2-fold lower than previously estimated from reversal potential measurements. Interestingly, a quite high fractional Ca²⁺ current of 1.4% was determined for the linearly conducting AMPA/kainate receptor channels found in these neurons.

References (56)

D.M. Armstrong et al.
Development of cholinergic neurons in the septal/diagonal band complex of the rat
Brain Res.
(1987)
P. Ascher et al.
Electrophysiological studies of NMDA receptors
Trends Neurosci.
(1987)
D.W. Choi
Glutamate neurotoxicity and diseases of the nervous system
Neuron
(1988)
G. Grynkiewicz et al.
A new generation of Cal' indicators with greatly improved fluorescence properties
J. Biol. Chem.
(1985)
Q.A. Gu et al.
Blockade of NMDA receptors prevents ocularity changes in kitten visual cortex after reversed monocular deprivation
Dev. Brain Res.
(1989)
A.B. MacDermott et al.
Receptors, ion channels and synaptic potentials underlying the integrative actions of excitatory amino acids
Trends Neurosci.
(1987)
M.G. Marciani et al.
Aspartateinduced changes in extracellular free calcium in ‘in vitro’ hippocampal slices of rat
Brain Res.
(1982)
M.L. Mayer et al.
The physiology of excitatory amino acids in the vertebrate central nervous system
Prog. Neurobiol.
(1987)
B. Meldrum et al.
Excitatory amino acid neurotoxicity and neurodegenerative disease
Trends Pharmacol. Sci.
(1990)
H. Miyakawa et al.
Synaptically activated increases in Ca²⁺ concentration in hippocampal CAI pyramidal cells are primarily due to voltage-gated Cal' channels
Neuron
(1992)

A. Obenaus et al.

DantroleneNa (Dantrium) blocks induction of long-term potentiation in hippocampal slices

Neurosci. Lett.

(1989)

H.U. Zeilhofer et al.

Inhibition of high voltage-activated calcium currents by l-glutamate receptor-mediated calcium influx

Neuron

(1993)

T.G.J. Allen et al.

The whole-cell calcium current in acutely dissociated magnocellularcholinergic basal forebrain neurones of the rat

J. Physiol.

(1993)

P. Ascher et al.

The role of divalent cations in the N-methyl-d-aspartate responses of mouse central neurones in culture

J. Physiol.

(1988)

T.V.P. Bliss et al.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

(1993)

N. Burnashev et al.

Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor

Science

(1992)

E. Carbone et al.

A low-voltage-activated fully inactivating Ca channel in vertebrate sensory neurones

Nature

(1984)

A. Castellano et al.

Sodium and calcium currents in dispersed mammalian septal neurons

J. Gen. Physiol.

(1991)

G.L. Collingridge et al.

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus

J. Physiol.

(1983)

F.A. Edwards et al.

A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system

Pflügers Arch.

(1989)

A.S. Finkel et al.

The synaptic current evoked in cat spinal motoneurones by impulses in single group la axons

J. Physiol.

(1983)

A.P. Fox et al.

Kinetics and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones

J. Physiol.

(1987)

T.A. Gilbertson et al.

Permeation of calcium ions through non-NMDA glutamate channels in retinal bipolar cells

Science

(1991)

O. Hamill et al.

Improved patch clamp techniques for high-resolution current recording from cells and cell-free membrane patches

Pflügers Arch.

(1981)

P. Hess et al.

Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependenceof singlechannel current in ventricular heart cells

J. Gen. Physiol.

(1986)

S. Hestrin et al.

Analysis of excitatory synaptic action in pyramidal cells using whole-cell recordings from rat hippocampal slices

J. Physiol.

(1990)

M. Hollmann et al.

Ca²⁺ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition

Science

(1991)

T. Honoré et al.

Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists

Science

(1988)

Cited by (247)

The GluN3 subunit regulates ion selectivity within native N-methyl-D-aspartate receptors
2020, IBRO Reports
Citation Excerpt :
While the permeability of divalent Ca2+ (PCa2+) relative to monovalent Cs+ (PCs+ assumed 1), estimated through optimal fits of the data using the extended GHK constant-field equation (Mayer ML and Westbrook GL, 1987), for NMDARs at L1 inputs was similar to PCa2+ for NMDARs at Str inputs (9 ± 3 vs. 7 ± 2 respectively; p = 0.6, t-test; n = 6 cells), the relative permeability of Na+ (PNa+, kept a free parameter) for the same receptors at L1 inputs was significantly smaller than PNa+ for receptors at Str inputs (0.2 ± 0.1 vs. 0.8 ± 0.1 respectively; p < 0.005, t-test). Thus, relative to Na+, the GluN1, GluN2B and GluN3A containing t-NMDARs at L1 inputs are ∼5-fold more permeable to Ca2+ than the GluN1/GluN2A-containing NMDARs at Str inputs (PCa2+/PNa+ or the fractional Ca2+ current (Schneggenburger et al., 1993), for L1 ≥ PCa2+/PNa+ for Str). Additionally, these data confirm that GluN3 containing t-NMDARs at L1 inputs are not only permeable to Ca2+, they are selective for Ca2+ over Na+ (0 < PNa+ << 1), as corroborated by the hyperpolarized non-zero Erev of their EPSCs, in contrast with the non-GluN3 containing d-NMDARs at Str inputs.
Glutamatergic N-methyl-d-aspartate receptors (NMDARs) are heterotetrameric proteins whose subunits are derived from three gene families, GRIN1 (codes for GluN1), GRIN2 (GluN2) and GRIN3 (GluN3). In addition to providing binding sites for glutamate and the co-agonist glycine, these subunits in their di (d-) and tri (t-) heteromeric configurations regulate various aspects of receptor function in the brain. For example, the decay kinetics of NMDAR-mediated synaptic currents depend on the type of GluN2 subunit (GluN2A-GluN2D) in the receptor subunit composition. While much is known about the contributions of GluN1 and GluN2 to d-NMDAR function, we know comparatively little about how GluN3 influences the function of t-NMDARs composed of one or more subunits from each of the three gene families. We report here that in addition to altering kinetics and voltage-dependent properties, the GluN3 subunit endows these receptors with ion selectivity wherein influx of Ca²⁺ is preferred over Na⁺. This became apparent in the process of assessing Ca²⁺ permeability through these receptors and is of significance given that NMDARs are generally believed to be nonselective to cations and increased selectivity can lead to enhanced permeability. This was true of two independent brain regions where t-NMDARs are expressed, the somatosensory cortex, where both receptor subtypes are expressed at separate inputs onto single neurons, and the entorhinal cortex, where they are co-expressed at individual synaptic inputs. Based on this data and the sequence of amino acids lining selectivity filters within these subunits, we propose GluN3 to be a regulatory subunit for ion selectivity in t-NMDARs.
An Inconvenient Truth: Calcium Sensors Are Calcium Buffers
2018, Trends in Neurosciences
Recent advances in Ca²⁺ imaging have given neuroscientists a tool to follow the activity of large numbers of individual neurons simultaneously in vivo in the brains of animals as they are presented with sensory stimulation, respond to environmental challenges, and engage in behaviors. The Ca²⁺ sensors used to transduce changes in cellular Ca²⁺ into changes in fluorescence must bind Ca²⁺ to produce a signal. By binding Ca²⁺, these sensors can act as buffers, often reducing the magnitude of a Ca²⁺ change severalfold, and producing a proportional slowing of the rates of change. Ca²⁺ probes can thus distort the patterns of activity they are intended to study and modify ongoing Ca²⁺ signaling functions. Recognizing these factors will enhance the use of in vivo Ca²⁺ imaging in the investigation of neural circuit function.
Resident Calmodulin Primes NMDA Receptors for Ca2+-Dependent Inactivation
2017, Biophysical Journal
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.
Quantifying Ca2+ current and permeability in ATP-gated P2X7 receptors
2015, Journal of Biological Chemistry
ATP-gated P2X7 receptors are prominently expressed in inflammatory cells and play a key role in the immune response. A major consequence of receptor activation is the regulated influx of Ca²⁺ through the self-contained cation non-selective channel. Although the physiological importance of the resulting rise in intracellular Ca²⁺ is universally acknowledged, the biophysics of the Ca²⁺ flux responsible for the effects are poorly understood, largely because traditional methods of measuring Ca²⁺ permeability are difficult to apply to P2X7 receptors. Here we use an alternative approach, called dye-overload patch-clamp photometry, to quantify the agonist-gated Ca²⁺ flux of recombinant P2X7 receptors of dog, guinea pig, human, monkey, mouse, rat, and zebrafish. We find that the magnitude of the Ca²⁺ component of the ATP-gated current depends on the species of origin, the splice variant, and the concentration of the purinergic agonist. We also measured a significant contribution of Ca²⁺ to the agonist-gated current of the native P2X7Rs of mouse and human immune cells. Our results provide cross-species quantitative measures of the Ca²⁺ current of the P2X7 receptor for the first time, and suggest that the cytoplasmic N terminus plays a meaningful role in regulating the flow of Ca²⁺ through the channel.
Extracellular Ca2+ per se inhibits quantal size of catecholamine release in adrenal slice chromaffin cells
2014, Cell Calcium
Classic calcium hypothesis states that depolarization-induced increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) triggers vesicle exocytosis by increasing vesicle release probability in neurons and neuroendocrine cells. The extracellular Ca²⁺, in this calcium hypothesis, serves as a reservoir of Ca²⁺ source. Recently we find that extracellular Ca²⁺ per se inhibits the [Ca²⁺]_i dependent vesicle exocytosis, but it remains unclear whether quantal size is regulated by extracellular, or intracellular Ca²⁺ or both [1]. In this work we showed that, in physiological condition, extracellular Ca²⁺ per se specifically inhibited the quantal size of single vesicle release in rat adrenal slice chromaffin cells. The extracellular Ca²⁺ in physiological concentration (2.5 mM) directly regulated fusion pore kinetics of spontaneous quantal release of catecholamine. In addition, removal of extracellular Ca²⁺ directly triggered vesicle exocytosis without eliciting intracellular Ca²⁺. We propose that intracellular Ca²⁺ and extracellular Ca²⁺ per se cooperately regulate single vesicle exocytosis. The vesicle release probability was jointly modulated by both intracellular and extracellular Ca²⁺, while the vesicle quantal size was mainly determined by extracellular Ca²⁺ in chromaffin cells physiologically.
PHYSIOLOGY OF INTRACELLULAR CALCIUM BUFFERING
2023, Physiological Reviews

View all citing articles on Scopus

^†: Present address: Department of Medicine, Renal Division, The Jewish Hospital of St. Louis, St. Louis, Missouri 63110.

View full text

Neuron

ArticleFractional contribution of calcium to the cation current through glutamate receptor channels

Abstract

Brain Res.

Trends Neurosci.

Neuron

J. Biol. Chem.

Dev. Brain Res.

Trends Neurosci.

Brain Res.

Prog. Neurobiol.

Trends Pharmacol. Sci.

Neuron

Neurosci. Lett.

Neuron

The whole-cell calcium current in acutely dissociated magnocellularcholinergic basal forebrain neurones of the rat

J. Physiol.

The role of divalent cations in the N-methyl-d-aspartate responses of mouse central neurones in culture

J. Physiol.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Control by asparagine residues of calcium permeability and magnesium blockade in the NMDA receptor

Science

A low-voltage-activated fully inactivating Ca channel in vertebrate sensory neurones

Nature

Sodium and calcium currents in dispersed mammalian septal neurons

J. Gen. Physiol.

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus

J. Physiol.

A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system

Pflügers Arch.

The synaptic current evoked in cat spinal motoneurones by impulses in single group la axons

J. Physiol.

Kinetics and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones

J. Physiol.

Permeation of calcium ions through non-NMDA glutamate channels in retinal bipolar cells

Science

Improved patch clamp techniques for high-resolution current recording from cells and cell-free membrane patches

Pflügers Arch.

Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependenceof singlechannel current in ventricular heart cells

J. Gen. Physiol.

Analysis of excitatory synaptic action in pyramidal cells using whole-cell recordings from rat hippocampal slices

J. Physiol.

Ca2+ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition

Science

Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists

Science

Article
Fractional contribution of calcium to the cation current through glutamate receptor channels

Ca²⁺ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition