title: Leptin-mediated ion channel regulation: PI3K pathways, physiological role, and therapeutic potential.
abstract: Leptin is produced by adipose tissue and identified as a "satiety signal," informing the brain when the body has consumed enough food. Specific areas of the hypothalamus express leptin receptors (LEPRs) and are the primary site of leptin action for body weight regulation. In response to leptin, appetite is suppressed and energy expenditure allowed. Beside this hypothalamic action, leptin targets other brain areas in addition to neuroendocrine cells. LEPRs are expressed also in the hippocampus, neocortex, cerebellum, substantia nigra, pancreatic β-cells, and chromaffin cells of the adrenal gland. It is intriguing how leptin is able to activate different ionic conductances, thus affecting excitability, synaptic plasticity and neurotransmitter release, depending on the target cell. Most of the intracellular pathways activated by leptin and directed to ion channels involve PI3K, which in turn phosphorylates different downstream substrates, although parallel pathways involve AMPK and MAPK. In this review we will describe the effects of leptin on BK, KATP, KV, CaV, TRPC, NMDAR and AMPAR channels and clarify the landscape of pathways involved. Given the ability of leptin to influence neuronal excitability and synaptic plasticity by modulating ion channels activity, we also provide a short overview of the growing potentiality of leptin as therapeutic agent for treating neurological disorders.
authors.affiliation: a Department of Drug Science , Lab of Cellular Physiology and Molecular Neuroscience, NIS Center of Excellence, University of Torino , Torino , Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gavello
authors.affiliation: a Department of Drug Science , Lab of Cellular Physiology and Molecular Neuroscience, NIS Center of Excellence, University of Torino , Torino , Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Carbone
authors.affiliation: a Department of Drug Science , Lab of Cellular Physiology and Molecular Neuroscience, NIS Center of Excellence, University of Torino , Torino , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Carabelli
mesh_terms: D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D006801:Humans; D007473:Ion Channels / Q000378:metabolism* / Q000502:physiology; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction; D009435:Synaptic Transmission
chemical_list: D000700:Analgesics; D000927:Anticonvulsants; D000928:Antidepressive Agents; D007473:Ion Channels; D020738:Leptin; D054411:Receptors, Leptin; D019869:Phosphatidylinositol 3-Kinases
keywords: Ca2+ and TRP channels; KATP and BK channels; Leptin; NMDA and AMPA receptors; PI3K; cell firing