Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

Abstract

One of the major targets for ethanol (alcohol) in the brain is the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated ion channel. Intriguingly, the effects of ethanol on the NMDA receptor are not homogeneous throughout the brain. This review focuses on recent studies revealing molecular mechanisms that mediate the actions of ethanol on the NMDA receptor in different brain regions via changes in NMDA receptor phosphorylation and compartmentalization. Specifically, the role of the scaffolding protein RACK1 and the regulatory protein DARPP-32 in mediating the distinct effects of ethanol is presented. KeywordsN-methyl-D-aspartate (NMDA); Ethanol; Phosphorylation; RACK1; Alcoholism is a devastating disease that affects 14 million people in the United States alone and costs society $165 billion a year. Alcoholism is defined as uncontrolled consumption of alcohol (ethanol) despite the negative consequences. The disease manifests itself or results from phenotypes such as tolerance, dependence, and withdrawal and/or craving. Considerable effort has been focused on elucidating the mechanisms that underlie the development and maintenance of alcohol addiction. Interestingly, although ethanol is a small diffusible molecule ( Fig. 1), only a defined number of targets have been identified that are altered as the result of acute or chronic exposure of neurons to ethanol (Fig. 1). Even more intriguing is the fact that ethanol affects the same targets differently in different brain regions. In this review, I will present examples of how signaling events that regulate the phosphorylation state and compartmentalization of proteins determine the activities of ethanol on the N-methyl-Daspartate (NMDA) receptor (NMDAR). Posttranslation Modification: Phosphorylation/DephosphorylationThe most common posttranslation modification is the addition of a phosphate group to the serine, threonine, or tyrosine residues of a protein substrate. This reaction, termed phosphorylation, is achieved via activation of protein kinases, which are divided into three groups: serine/threonine kinases, tyrosine kinases, and dual-specificity kinases, which are able to phosphorylate all three residues. The opposite reaction, in which a phosphate group is removed from a protein (dephosphorylation), is performed by either serine/threonine or tyrosine phosphatases. Receptor kinases and phosphatases are integral parts of the plasma membrane, whereas nonreceptor kinases and phosphatases reside intracellularly, with their subcellular compartmentalization determined in large part by protein-lipid or protein-protein interactions, as will be discussed in sections 3 and 6. Kinases and phosphatases are specifically Address correspondence to: Dorit Ron, Ernest Gallo Center, 5858 Horton St., Suite 200, Emeryville,.. NIH Public Access Author ManuscriptNeuroscientist. Author manuscript; available in PMC 2006 February 7. Published in final edited form as:Neuroscientist. 2004 August ; 10(4): 325-336. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ...

Developmentally Regulated Actions of Alcohol on Hippocampal Glutamatergic Transmission

“…It should be noted that, given that intracellular signaling pathways are likely to be affected during whole-cell patch-clamp recordings and these modulate sensitivity of NMDARs to ethanol (Ron, 2004), it is possible that the sensitivity of these receptors is altered under whole-cell patch clamping. This uncertainty must be kept in mind when interpreting our results.…”

Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior

“…The NR2 subunits are phosphorylated by the Src family protein tyrosine kinases (PTKs) Fyn and Src (Salter and Kalia, 2004), leading to upregulation of channel function (Salter and Kalia, 2004). The actions of ethanol on the NMDAR are also regulated by phosphorylation of the subunits (Ron, 2004).…”

“…The NMDAR is a major target of ethanol (Kumari and Ticku, 2000;Ron, 2004), and this receptor has been implicated in ethanol-associated phenotypes such as tolerance, dependence, withdrawal, craving, and relapse (Krystal et al, 2003). For example, NMDAR antagonists block the development of rapid tolerance to ethanol (Khanna et al, 1993), decrease ethanol intake (Holter et al, 2000), and reduce the intensity of ethanol withdrawal symptoms (Bisaga et al, 2000).…”

A Molecular Mechanism of Ethanol Dependence: The Influence of the Ionotropic Glutamate Receptor Activated by N-Methyl-D-Aspartate

“…iGluR-NMDA function is inhibited by ethanol in a concentration-dependent manner over the range of 5-50 mM. This is also the concentration range that produces intoxication and that is linearly related to the intoxication potency (Ron, 2004). This suggests that ethanolinduced inhibition of responses to the iGluR-NMDA activation may contribute to the neural and the cognitive impairments associated with alcohol intoxication.…”