Most neurons are influenced by multiple neuromodulatory inputs that converge on common effectors. Mechanisms that route these signals are key to selective neuromodulation but are poorly understood. G protein-gated inwardly rectifying K (GIRK or Kir3) channels mediate postsynaptic inhibition evoked by G protein-coupled receptors (GPCRs) that signal via inhibitory G proteins.
View Article and Find Full Text PDFAlzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein-gated inwardly rectifying K (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology.
View Article and Find Full Text PDFSince the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment.
View Article and Find Full Text PDFG protein-gated inwardly rectifying K (GIRK/Kir3) channels exert a critical inhibitory influence on neurons. Neuronal GIRK channels mediate the G protein-dependent, direct/postsynaptic inhibitory effect of many neurotransmitters including γ-aminobutyric acid (GABA), serotonin, dopamine, adenosine, somatostatin, and enkephalin. In addition to their complex regulation by G proteins, neuronal GIRK channel activity is sensitive to phosphatidylinositol 4,5-bisphosphate (PIP), phosphorylation, regulator of G protein signaling (RGS) proteins, intracellular Na and Ca, and cholesterol.
View Article and Find Full Text PDFWnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses.
View Article and Find Full Text PDFSystemic administration of ML297, a selective activator of G-protein-gated inwardly rectifying K (GIRK) channels, decreases innate avoidance behavior in male C57BL/6J mice. The cellular mechanisms mediating the ML297-induced suppression of avoidance behavior are unknown. Here, we show that systemic ML297 administration suppresses elevated plus maze (EPM)-induced neuronal activation in the ventral hippocampus (vHPC) and basolateral amygdala (BLA) and that ML297 activates GIRK1-containing GIRK channels in these limbic structures.
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