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Leptin Activates Transient Receptor Potential Melastatin 7 (TRPM7) Channels in Leptin‐Receptor Expressing Pheochromocytoma (PC12) Cells
Author(s) -
Liu XiaoRu,
Paudel Omkar,
Shin MiKyung,
Tang WanYee,
Shirahata Machiko,
Polotsky Vsevolod Y.,
Sham James S.K.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1039.6
Subject(s) - trpm7 , endocrinology , medicine , transient receptor potential channel , leptin , carotid body , chemistry , leptin receptor , trpv , agonist , ion channel , receptor , electrophysiology , biology , trpv1 , obesity
Obesity is a leading cause of high cardiovascular morbidity and mortality. It is characterized by an increased leptin level, which has been implicated in increased sympathetic activity and the pathogenesis of hypertension. However, the mechanism by which leptin enhances sympathetic activity is unclear. Leptin receptors (LEPRs) are expressed in the carotid bodies, the most important arterial chemoreceptors for the cardiovascular‐respiratory chemoreflex. We have previously demonstrated that leptin enhances carotid sinus nerve activity in response to hypoxia; this effect is abolished by non‐selective blockers of transient receptor potential (TRP) channels; and the TRPM7 channel is the most abundant TRP subtype expressed in CB (Shirahata et al., Adv Exp Med Biol. 2015;860:153–9). Since leptin is known to regulate many different ion channels, we hypothesize that leptin may exert its effects through modulation of TRPM7 channel activity. To test this hypothesis, we used LEPR (LEPRb) expressing pheochromocytoma (PC12 LEPRb ) cells, which express a high level of TRPM7 channels, as the cell model. Non‐selective cation channels were recorded under amphotericin‐B perforated‐patch techniques with K + replaced by Cs + in the presence of voltage‐gated Ca 2+ channel and Cl − channel blockers. Voltage‐ramp from −100 to 100 mV activated an outward‐rectifying current. Removal of extracellular divalent ions enhanced the inward current, consistent with the inward divalent ion selectivity of TRPM7. The specific TRPM7 agonist naltriben caused significant increase of the current, which was abolished by the TRPM7 antagonist NS8593 and FTY720, indicating that functional TRPM7 channels are present in PC12 LEPRb cells. More importantly, leptin at concentration of 10–100 ng/ml caused concentration‐dependent increase in the outward rectifying current. The enhanced current was completely blocked by NS8593 and FTY720. These results for the first time demonstrated that stimulation of leptin receptor is capable of activating TRPM7 channels, and suggest that leptin may exert its physiological effects through modulation of TRPM7 activity. Support or Funding Information This work is supported by the NIH grant HL133100