Mechanisms of blockade of excitatory amino acid receptor channels

doi:10.1016/0165-6147(90)90070-O

Trends in Pharmacological Sciences

Volume 11, Issue 4, April 1990, Pages 167-172

https://doi.org/10.1016/0165-6147(90)90070-O Get rights and content

Abstract

Ion channels coupled to NMDA, kainate and AMPA receptors are the target of pharmacological regulation by a variety of drugs and ions. While these channels are all nonselectively permeated by Na⁺ and K⁺ ions, the NMDA receptor-channel complex contains a number of pharmacological sites distinct from those found on the others. For example, Mg²⁺ ions rapidly and reversibly block open NMDA channels in a highly voltage-dependent manner. Its extreme voltage dependence suggests that the Mg²⁺ binding site lies deep within the ion channel pore. By contrast the voltage-dependent block of activated channels by the dissociative anesthetic 'slow channel blockers' has unusual characteristics. In the fourth article in our series on excitatory amino acids, John MacDonald and Linda Nowak analyse the characteristics of these two types of block and describe the hypotheses that have been put forward to explain the mechanisms involved.

References (34)

J.C. Watkins et al.
Trends Pharmacol. Sci.
(1990)
N. Akaike et al.
Neurosci. Lett.
(1988)
E.R. Liman et al.
Brain Res.
(1989)
N.I. Kiskin et al.
Neurosci. Lett.
(1986)
N. Akaike
Neurosci. Lett.
(1987)
Z. Miljkovic et al.
Brain Res.
(1986)
C.R. Honey et al.
Neurosci. Lett.
(1985)
J.A. Kemp et al.
Trends Neurosci.
(1987)
E. Sernagor et al.
Neuron
(1989)
D.T. Monaghan et al.
Annu. Rev. Pharmacol. Toxicol.
(1989)

P. Ascher et al.

J. Physiol. (London)

(1988)

M.L. Mayer et al.

J. Physiol. (London)

(1987)

P. Ascher et al.

J. Physiol. (London)

(1988)

S.G. Cull-Candy et al.

J. Physiol. (London)

(1989)

I. Llano et al.

J. Lerma et al.

J.F. MacDonald et al.

J. Physiol. (London)

(1989)

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Trends in Pharmacological Sciences

Mechanisms of blockade of excitatory amino acid receptor channels

Abstract

Trends Pharmacol. Sci.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Trends Neurosci.

Neuron

Annu. Rev. Pharmacol. Toxicol.

J. Physiol. (London)

J. Physiol. (London)

J. Physiol. (London)

J. Physiol. (London)

J. Physiol. (London)