Journal Article

KCNN Genes that Encode Small-Conductance Ca super(2+)-Activated K super(+) Channels Influence Alcohol and Drug Addiction

Padula, Audrey E, McGuier, Natalie S, Randall, Patrick K, Williams, Robert W, Nimitvilai, Sudarat, Becker, Howard C, Griffin, William C, Mulholland, Patrick J, Chesler, Elissa J, Miles, Michael F, Woodward, John J, Lopez, Marcelo F, Cannady, Reginald

2015

Overview

Small-conductance Ca super(2+)-activated K super(+) (K sub(Ca)2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode K sub(Ca)2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the K sub(Ca)2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of K sub(Ca)2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. K sub(Ca)2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.