Abstract
Ionotropic glutamate receptors (iGluR) are ligand-gated ion channels and are densely expressed in broad areas of mammalian brains. Like iGluRs, acid-sensing ion channels (ASIC) are ligand (H+)-gated channels and are enriched in brain cells and peripheral sensory neurons. Both ion channels are enriched at excitatory synaptic sites, functionally coupled to each other, and subject to the modulation by a variety of signaling molecules. Central among them is a gasotransmitter, nitric oxide (NO). Available data show that NO activity-dependently modulates iGluRs and ASICs via either a direct or an indirect pathway. The former involves a NO-based and cGMP-independent post-translational modification (S-nitrosylation) of extracellular cysteine residues in channel subunits or channel-interacting proteins. The latter is achieved by NO activation of soluble guanylyl cyclase, which in turn triggers an intracellular cGMP-sensitive cascade to indirectly modulate iGluRs and ASICs. The NO modification is usually dynamic and reversible. Modified channels undergo significant, interrelated changes in biochemistry and electrophysiology. Since NO synthesis is enhanced in various neurological disorders, the NO modulation of iGluRs and ASICs is believed to be directly linked to the pathogenesis of these disorders. This review summarizes the direct and indirect modifications of iGluRs and ASICs by NO and analyzes the role of the NO-iGluR and NO-ASIC coupling in cell signaling and in the pathogenesis of certain related neurological diseases.
Highlights
Ionotropic glutamate receptors are ligand-gated cation ion channels. They are classified into N -methyl-d-aspartate receptors (NMDAR), α-amino-3-hydroxy-5-methylisoxazole-4propionic acid receptors (AMPAR), and kainate receptors (Dingledine et al, 1999)
The direct pathway involves a nitric oxide (NO)-based post-translational modification of Ionotropic glutamate receptors (iGluR) and acid-sensing ion channels (ASIC) proteins, i.e., S-nitrosylation. This biochemical reaction occurs when a nitrosyl group is added to the thiol side-chain of cysteine residues to form S-nitrosothiols, leading to changes in tertiary structure and function of modified iGluRs and ASICs (Sen and Snyder, 2010)
This review will discuss current progress in understanding the modulation of iGluRs and ASICs by NO. We reviewed these two types of channels together because (1) they are co-localized in the confined postsynaptic density microdomain (Zha et al, 2006), (2) they are functionally coupled to each other to contribute to neurological disorders involving excessive glutamate release and acidosis (Gao et al, 2005), and (3) they show some common properties in the regulation by NO
Summary
Ionotropic glutamate receptors (iGluR) are ligand-gated cation ion channels They are classified into N -methyl-d-aspartate receptors (NMDAR), α-amino-3-hydroxy-5-methylisoxazole-4propionic acid receptors (AMPAR), and kainate receptors (Dingledine et al, 1999). As a major group of excitatory receptors, iGluRs are critical for normal operations of cellular and synaptic activity and plasticity Malfunction of these ion channels is frequently linked to the pathogenesis of a wide range of neurological disorders (Dingledine et al, 1999). ASICs are a distinct family of proton (H+)-gated, voltage-independent, and cation (Na+)-selective channels They are broadly expressed in peripheral sensory neurons and CNS neurons (Waldmann et al, 1997a,b; Alvarez de la Rosa et al, 2003). Increasing evidence shows that NO can modulate iGluRs and ASICs through a direct (cGMP-independent) or an indirect (cGMP-dependent) pathway (Ahern et al, 2002)
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