Regulation of neuronal chloride homeostasis by neuromodulators

Abstract

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.

Ionotropic and metabotropic kainate receptor signalling regulates Cl− homeostasis and GABAergic inhibition

“…It was also abolished via blockade of metabotropic KAR signalling with GDP-β-S, suggesting that G-proteins are necessary for this process, and was also shown to be independent of zinc release at MF-CA3 terminals. This finding is in line with a growing body of literature suggesting that KCC2 activity can be regulated by a number of different receptors that signal via G-proteins, including mGluRs and mZnRs (Banke and Gegelashvili, 2008, Chorin et al 2011, Gilad et al 2015, Mahadevan and Woodin, 2016. KARs, similar to mGluRs and mZnRs, activate a G-protein signalling pathway that increases PKC activity (Melyan et al 2002, Lerma andMarques, 2013).…”

“…The metabotropic signalling mode, which we have shown regulates E GABA and is dependent on KCC2 transporter activity, places KARs on a growing list of proteins that are able to regulate KCC2 via G‐protein signalling (Banke and Gegelashvili, , Chorin et al . , Mahadevan and Woodin, ). Two previous studies have reported an increase in transporter activity and expression of KCC2 upon KA application (Khirug et al .…”

“…The two signalling modes of KARs may serve different functional roles for chloride homeostasis, allowing the cell to regulate the strength of GABAergic inhibition in response to excitatory activity in both a KCC2-dependent and KCC2 independent manner. The metabotropic signalling mode, which we have shown regulates E GABA and is dependent on KCC2 transporter activity, places KARs on a growing list of proteins that are able to regulate KCC2 via G-protein signalling (Banke and Gegelashvili, 2008, Chorin et al 2011, Mahadevan and Woodin, 2016. Two previous studies have reported an increase in transporter activity and expression of KCC2 upon KA application (Khirug et al 2010, Gilad et al 2015, although the possibility that KARs themselves might serve as the locus of action has not been examined.…”

“…, Gilad et al . , Mahadevan and Woodin, ). KARs, similar to mGluRs and mZnRs, activate a G‐protein signalling pathway that increases PKC activity (Melyan et al .…”

KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

“…Thus, Ca 2+ influx through postsynaptic NMDA receptors or during prolonged postsynaptic firing 6 rapidly reduces KCC2 membrane expression and function through protein phosphatase 1-dependent dephosphorylation of its Ser940 residue and protein cleavage by the calcium-activated protease calpain 7,8,9 . Conversely, chloride influx through GABAA receptors stabilizes KCC2 at the plasma membrane via chloride-mediated inhibition of the serine/threonine WNK1 kinase and its downstream effectors SPAK/OSR1, which phosphorylate KCC2 on Thr906 and Thr1007 residues 10,11,12 . Finally, KCC2 expression is also regulated by several neuromodulators acting on G-protein couples receptors 13 as well as neurotrophins such as BDNF acting via TrkB signaling 14 .…”