JNK Pathway Activation Is Controlled by Tao/TAOK3 to Modulate Ethanol Sensitivity

Abstract

Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. Here we demonstrate that JNK signaling functions downstream of the Sterile20 kinase family gene tao/Taok3 to regulate the behavioral effects of acute ethanol exposure in both the fruit fly Drosophila and mice. In flies tao is required in neurons to promote sensitivity to the locomotor stimulant effects of acute ethanol exposure and to establish specific brain structures. Reduced expression of key JNK pathway genes substantially rescued the structural and behavioral phenotypes of tao mutants. Decreasing and increasing JNK pathway activity resulted in increased and decreased sensitivity to the locomotor stimulant properties of acute ethanol exposure, respectively. Further, JNK expression in a limited pattern of neurons that included brain regions implicated in ethanol responses was sufficient to restore normal behavior. Mice heterozygous for a disrupted allele of the homologous Taok3 gene (Taok3Gt) were resistant to the acute sedative effects of ethanol. JNK activity was constitutively increased in brains of Taok3Gt/+ mice, and acute induction of phospho-JNK in brain tissue by ethanol was occluded in Taok3Gt/+ mice. Finally, acute administration of a JNK inhibitor conferred resistance to the sedative effects of ethanol in wild-type but not Taok3Gt/+ mice. Taken together, these data support a role of a TAO/TAOK3-JNK neuronal signaling pathway in regulating sensitivity to acute ethanol exposure in flies and in mice.

Rsu1 regulates ethanol consumption in Drosophila and humans

“…Because Rsu1 acts in concert with PINCH to inhibit JNK activity during development (17), we tested for potential genetic interactions between mutations in ics and basket (encoding JNK). We were unable to find any such interaction or a sedation phenotype in basket mutants, which is consistent with two previous studies reporting the absence of an ethanol sedation phenotype in basket mutants (22,23). Other than JNK, other downstream targets of integrin signaling include Rho family GTPases.…”

The Genetics of Alcohol Responses of Invertebrate Model Systems

“…A loss-of-function mouse mutant of Taok3 shows resistance to the intoxicating effects of ethanol, the same that is seen with subcutaneous systemic injection of a JNK inhibitor. Importantly, that pharmacologic effect was occluded in Taok3 mutant mice, indicating that Taok3 indeed acts via JNK (Kapfhamer et al, 2012). Together, these findings show that the proper function and dynamics of the cytoskeleton are important during development, for adult neuronal function, and ultimately for behavioral responses to drugs of abuse.…”

“…Unlike some of the previously mentioned regulators of actin dynamics, Tao is required during development and not in the adult fly (King et al, 2011), indicating that the kinase is involved in setting up ethanol-responsive circuitry. Tao acts through the Jun N-terminal MAP kinase, JNK, to regulate ethanol-induced hyperactivity and brain morphology (Kapfhamer et al, 2012). A loss-of-function mouse mutant of Taok3 shows resistance to the intoxicating effects of ethanol, the same that is seen with subcutaneous systemic injection of a JNK inhibitor.…”

Genome wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood

“…41 TAOK3 activates p38, inhibits cJun NH 2 -terminal kinase (JNK) signaling, 42 and is a member of the mitogen activated protein kinase (MAPK) cascade, affecting fundamental cellular signaling pathways. JNK and MAPK signal transduction pathways are activated by obesity and are required for obesity-induced insulin resistance.…”