Nicotine combined with estrogen activates protein kinase PKCι and TAO, while inhibiting specific MAP kinase pathways in cultured human neurons: an atlas of kinase activities for nicotine use disorder.

Introduction: Women exhibit sex-specific differences in their responses to nicotine, with sex hormones like estrogen and progesterone playing key roles in nicotine addiction among women. Nicotine disrupts neuronal firing in the brain's reward system, an effect regulated by estrogen. In this study, we hypothesized that exposing human female neurons to both nicotine and estrogen would activate distinct signaling pathways. Methods: We treated human female SH-SY5Y neurons with nicotine and estrogen, and compared these to treatments with each substance alone or vehicle control. Using PamGene PamStation technology, we created an atlas of over 500 kinase activities per sample. Results: We found that nicotine modulates MAP kinase pathways in a dichotomous manner. Estrogen showed unique kinase effects, and in combination with nicotine, elicited diverse pathway responses-some kinases becoming hyperactive and others hypoactive. Bioinformatics analysis highlighted several kinases as central to this combined signaling, including PKCɩ and TAO, which showed higher kinase activity only with combined treatment and have known links to behavior in rodent models. Conversely, kinases such as the insulin receptor (INSR), HER2, FAK1, and ABL1 exhibited decreased activity under combined treatment. Discussion: These findings reveal nicotine-specific kinase mechanisms and suggest potential targets for pharmacotherapy aimed particularly at females with high estrogen levels and nicotine use disorder.