TY - JOUR
T1 - Leptin excites proopiomelanocortin neurons via activation of TRPC channels
AU - Qiu, Jian
AU - Fang, Yuan
AU - Rønnekleiv, Oline K.
AU - Kelly, Martin J.
PY - 2010/1/27
Y1 - 2010/1/27
N2 - 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
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. Copyright
UR - http://www.scopus.com/inward/record.url?scp=75349092316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=75349092316&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4816-09.2010
DO - 10.1523/JNEUROSCI.4816-09.2010
M3 - Article
C2 - 20107083
AN - SCOPUS:75349092316
SN - 0270-6474
VL - 30
SP - 1560
EP - 1565
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 4
ER -