Purinergic Stimulation Induces Ca2+-dependent Activation of Na+-K+-2Cl- Cotransporter in Human Nasal Epithelia

Shin, Ji Hyun; Namkung, W.; Choi, Jae Young; Yoon, Joo Heon; Lee, Min Goo

doi:10.1074/jbc.m400639200

Cited by 18 publications

(10 citation statements)

References 28 publications

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“…Extracellular NH 4 + serves as a surrogate to K + and reverse KCC2-dependent transport of this molecule leads to a subsequent intracellular acidification (Titz et al 2006). Rates of steady-state NH 4 + influx, representing KCC2 activity, were determined by monitoring a 100 s period of the decrease in intracellular pH (Shin et al 2004; Hershfinkel et al 2009). …”

Section: Methodsmentioning

confidence: 99%

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Gilad

Shorer

Ketzef

et al. 2015

Neurobiology of Disease

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The aim of this study was to investigate the role of the synaptic metabotropic zinc receptor mZnR/GPR39 in physiological adaptation to epileptic seizures. We previously demonstrated that synaptic activation of mZnR/GPR39 enhances inhibitory drive in the hippocampus by upregulating neuronal K+/Cl− co-transporter 2 (KCC2) activity. Here, we first show that mZnR/GPR39 knockout (KO) adult mice have dramatically enhanced susceptibility to seizures triggered by a single intraperitoneal injection of kainic acid, when compared to wild type (WT) littermates. Kainate also substantially enhances seizure-associated gamma oscillatory activity in juvenile mZnR/GPR39 KO hippocampal slices, a phenomenon that can be reproduced in WT tissue by extracellular Zn2+ chelation. Importantly, kainate-induced synaptic Zn2+ release enhances surface expression and transport activity of KCC2 in WT, but not mZnR/GPR39 KO hippocampal neurons. Kainate-dependent upregulation of KCC2 requires mZnR/GPR39 activation of the Gαq/phospholipase C/extracellular regulated kinase (ERK1/2) signaling cascade. We suggest that mZnR/GPR39-dependent upregulation of KCC2 activity provides homeostatic adaptation to an excitotoxic stimulus by increasing inhibition. As such, mZnR/GPR39 may provide a novel pharmacological target for dampening epileptic seizure activity.

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Section: Methodsmentioning

confidence: 99%

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Gilad

Shorer

Ketzef

et al. 2015

Neurobiology of Disease

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“…This acidification in the presence of NH 4 Cl, results from NH 4 + influx at steady state and represents KCC2 activity. Rates of steady-state NH 4 + influx were determined by monitoring the initial 75 s period of the decrease in intracellular pH (Shin et al, 2004; Hershfinkel et al, 2009), thus minimizing the exposure to NH 4 Cl (Bonnet and Wiemann, 1999) and the potential effects of pH regulatory mechanisms. BCECF fluorescence was calibrated using 10 μ M nigericin in oxygenated (100% O 2 ) solution containing the following (in mM): 118 KCl, 3 NaCl, 1 MgCl 2 , 1.5 CaCl 2 , 25 HEPES, and 10 glucose (Ritucci et al, 1996; Trapp et al, 1996; Ruusuvuori et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Chorin¹,

Vinograd²,

Fleidervish³

et al. 2011

J. Neurosci.

125

172

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Vesicular Zn2+ regulates postsynaptic neuronal excitability upon its corelease with glutamate. We previously demonstrated that synaptic Zn2+ acts via a distinct metabotropic zinc-sensing receptor (mZnR) in neurons to trigger Ca2+ responses in the hippocampus. Here, we show that physiological activation of mZnR signaling induces enhanced K+/Cl− cotransporter 2 (KCC2) activity and surface expression. As KCC2 is the major Cl− outward transporter in neurons, Zn2+ also triggers a pronounced hyperpolarizing shift in the GABAA reversal potential. Mossy fiber stimulation-dependent upregulation of KCC2 activity is eliminated in slices from Zn2+ transporter 3-deficient animals, which lack synaptic Zn2+. Importantly, activity-dependent ZnR signaling and subsequent enhancement of KCC2 activity are also absent in slices from mice lacking the G-protein-coupled receptor GPR39, identifying this protein as the functional neuronal mZnR. Our work elucidates a fundamentally important role for synaptically released Zn2+ acting as a neurotransmitter signal via activation of a mZnR to increase Cl− transport, thereby enhancing inhibitory tone in postsynaptic cells.

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“…Cl − i /HCO 3 − o exchange activities were estimated from the initial rate of pH i increase as a result of Cl − o removal in the HCO 3 − containing buffer (25 mM HCO 3 − with a 5% CO 2 gassing). The intrinsic buffer capacity (β i ) was calculated by measuring ΔpH i in response to 5–40 mM NH 4 Cl pulses in Na-free solutions 18. The β i of HEK cells was 36.4 (2.2) mM/pH unit (at pH i 7.1), and this value was not significantly different for cells transfected with WT- or mutant-pendrins.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneity in the processing defect of SLC26A4 mutants

Yoon

Park²,

Yoo

et al. 2008

Journal of Medical Genetics

109

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Purinergic Stimulation Induces Ca2+-dependent Activation of Na+-K+-2Cl- Cotransporter in Human Nasal Epithelia

Abstract: Increasing evidence suggests that P2 receptors (P2Rs) in airway epithelial cells perform critical functions in auto-or paracrine regulation of fluid and mucus secretion. In the present study, we characterized the effects of P2R stimulation on Na

Cited by 18 publications

References 28 publications

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures

Upregulation of KCC2 Activity by Zinc-Mediated Neurotransmission via the mZnR/GPR39 Receptor

Heterogeneity in the processing defect of SLC26A4 mutants

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