Leptin excites proopiomelanocortin neurons via activation of TRPC channels

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Abstract

Leptin can exert its potent appetite-suppressing effects via activation of hypothalamic proopiomelanocortin (POMC) neurons. It depolarizes POMC neurons via activation of a yet unidentified nonselective cation current. Therefore, we sought to identify the conductance activated by leptin using whole-cell recording in EGFP-POMC neurons from transgenic mice. The TRPC channel blockers SKF96365 (1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H- imidazole hydrochloride), flufenamic acid, and 2-APB (2-aminoethyl diphenylborinate) potently inhibited the leptin-induced current. Also, lanthanum (La3+) and intracellular Ca2+ potentiated the effects of leptin. Moreover, the diacylglycerol-permeable analog OAG (2-acetyl-1-oleoyl-sn- glycerol) failed to activate any TRPC current. Using a Cs+-gluconate- based internal solution, the leptin-activated current reversed near -20 mV. After replacement of external Na+ and K+ with Cs +, the reversal shifted to near 0 mV, and the I/V curve exhibited a negative slope conductance at voltages more negative than -40 mV. Based on scRT-PCR, TRPC1 and TRPC4-7 mRNA were expressed in POMC neurons, with TRPC5 being the most prevalent. The leptin-induced current was blocked by the Jak2 inhibitor AG490, the PI3 kinase inhibitor wortmannin, and the phospholipase C inhibitors, U73122 and ET-18-OCH3. Notably, we identified PLCγ1 transcripts in the majority of POMC neurons. Therefore, leptin through a Jak2-PI3 kinase-PLCγ pathway activates TRPC channels, and TRPC1, 4, and 5 appear to be the key channels mediating the depolarizing effects of leptin in POMC neurons. Copyright

Original languageEnglish (US)
Pages (from-to)1560-1565
Number of pages6
JournalJournal of Neuroscience
Volume30
Issue number4
DOIs
StatePublished - Jan 27 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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