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

KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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“…2012; Gilad et al . 2015). In the CA3 region, the mossy fibre (MF) terminals form specialized synapses onto CA3 pyramidal neurons.…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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“…We first asked whether endogenous Zn 2+ levels were similar in WT and ZnR/GPR39 KO mice. Tissue samples from the distal colon were loaded with Zinpyr-1 [53–55] and fluorescent signals were monitored in the presence or absence (control) of the high-affinity cell permeable Zn 2+ chelator, TPEN (20 µM). The Zn 2+ -dependent fluorescence levels were similar in control tissues from WT or ZnR/GPR39 KO, and application of TPEN significantly attenuated the fluorescent signal, indicating that the signal is triggered by Zn 2+ .…”

Section: Resultsmentioning

confidence: 99%

“…6A – B), suggesting that Zn 2+ levels in colonocytes are similar in WT and ZnR/GPR39 KO mice. Using a similar approach it was previously shown that levels of neuronal vesicular Zn 2+ were not different in WT and ZnR/GPR39 KO tissue [55]. …”

Section: Resultsmentioning

confidence: 99%

“…While radioactive ions have been traditionally used to monitor the activity of the Cl − transporters, the fluorescent based live-imaging system allows similar analysis of net ion flux/accumulation with a very good temporal resolution in specific cells. Indeed, this paradigm has been well established in numerous papers [42–44,55,87,88]. Briefly, cells were perfused with Ringer’s solution (containing 120 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl 2 , 20 mM HEPES, 15 mM glucose, 1.5 mM CaCl 2 at pH 7.4) to obtain a stable baseline.…”

Section: Methodsmentioning

confidence: 99%

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The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

Sunuwar

Asraf

Donowitz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn2+ acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn2+ we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn2+ and ZnR/GPR39 are both required for a beneficial effect of Zn2+ in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl− transport, a critical factor in diarrhea, by upregulating K+/Cl− cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl− absorption pathway. Finally, inhibition of KCC-dependent Cl− transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn2+ acting via ZnR/GPR39 has a direct role in controlling Cl− absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.

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“…extracellular versus intracellular – might result in opposite consequences. Gilad et al (2015) investigate the role of zinc (Zn 2+ ) signaling in epileptic seizures induced by the excitotoxin kainic acid and unravel an adaptive mechanism enhancing the crucial inhibitory K + /Cl − cotransporter 2 (KCC2) through the synaptic metabotropic Zn 2+ receptor mZnR/GPR39. The authors propose that synaptic Zn 2+ released from glutamatergic terminals triggers the adaptive mechanism and might therefore exert a crucial neuroprotective function to restore inhibitory drive, preventing excitotoxicity during sustained seizures.…”

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confidence: 99%