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P2RX4

Official Full Name
purinergic receptor P2X, ligand-gated ion channel, 4
Background
The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel with high calcium permeability. The main pharmacological distinction between the members of the purinoceptor family is the relative sensitivity to the antagonists suramin and PPADS. The product of this gene has the lowest sensitivity for these antagonists. Multiple alternatively spliced transcript variants, some protein-coding and some not protein-coding, have been found for this gene. [provided by RefSeq, Feb 2012]
Synonyms
P2RX4; purinergic receptor P2X, ligand-gated ion channel, 4; P2X4; P2X4R; P2X purinoceptor 4; ATP receptor; purinoceptor P2X4; P2X receptor, subunit 4; purinergic receptor P2X4; ATP-gated cation channel protein

P2RX4 and Alcohol Use Disorders

Alcohol use disorders (AUDs) rank third on the list of preventable causes of morbidity in the United States, which is a major national impact that affects over 18 million people and causes over 100,000 deaths annually. Drug development for AUDs is a relatively young field compared to cancer, cardiovascular and psychiatric disorders. Ligand-gated ion channels (LGICs) play an important role in ethanol-induced behaviors and drinking. Within the mammalian CNS, there are two major purinergic receptor families that bind to adenine nucleotides including adenosine 5’-triphosphate (ATP), P2X family of LGICs, and the P2Y family of G protein-coupled receptors. Thus, purinergic P2X receptors (P2RXs) form functional heteromeric or homomeric receptor that modulate the release of other neurotransmitters.

P2RXs are distributed widely within the mammalian CNS in a heterogeneous fashion. P2RX4s localize to the hippocampal pyramidal layers CA1, CA2 and CA3 as well as the granule layers of the dentate gyrus, along with P2RX2s and P2RX6s. P2RX4s is the most robustly expressed functional ATP-gated purinergic receptors in the CNS. In addition to normal levels of expression, the P2RX4 has been reported to be altered by dopamine depletion, specifically in the 6-hydroxydopamine rat model of Parkinson’s disease with decreased expression of SNpc and dorsal striatal GABAergic neurons and increased expression of SNpr GABAergic neurons. P2RX4 represents a novel and largely unexplored target for drug development to prevent AUDs and plays a role in regulating ethanol intake. There is an inverse relationship between P2RX4s activity and ethanol consumption.

P2RX4 Figure 1. The major connections within the reward and aversion circuitry are regulated by P2RX4s either directly or indirectly. (doi: 10.3389/fnins.2014.00176)

References:

  1. KelleM.Franklin, LianaAsatryan, MichaelW.Jakowec, JamesR.Trudell, RichardL.Bell and DarylL.Davies. (2014) 'P2X4 receptors (P2X4Rs) represent anovel target for the development of drugs to prevent and/or treat alcoholuse disorders', Frontiers in Neuroscience, 8:176.
  2. Bortolato,M., Yardley,M.M., Khoja,S., Godar,S.C., Asatryan,L. and Finn,D.A. (2013) 'Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin', Int.J. Neuropsychopharmacol, 16:1059-1070.
  3. Davies, D. L., Bortolato,M., Finn, D. A., Ramaker,M. J., Barak, S. and Ron, D. (2013) 'Recent advances in the discovery and preclinical testing of novel com- pounds for the prevention and/or treatment of alcohol use disorders', Alcohol. Clin. Exp. Res, 37: 8-15.

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