RT Journal Article
SR Electronic
T1 Leptin Excites Proopiomelanocortin Neurons via Activation of TRPC Channels
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1560
OP 1565
DO 10.1523/JNEUROSCI.4816-09.2010
VO 30
IS 4
A1 Jian Qiu
A1 Yuan Fang
A1 Oline K. Rønnekleiv
A1 Martin J. Kelly
YR 2010
UL http://www.jneurosci.org/content/30/4/1560.abstract
AB 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.