Activity-Dependent Cleavage of the K-Cl Cotransporter KCC2 Mediated by Calcium-Activated Protease Calpain

Puskarjov, Martin; Ahmad, Faraz; Kaila, Kai; Blaesse, Peter

doi:10.1523/jneurosci.6265-11.2012

Cited by 143 publications

(169 citation statements)

References 74 publications

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“…Graded gephyrin proteolysis provides a mechanism for activity-dependent, dynamic regulation of gephyrin scaffolds and, hence, GABAergic transmission 173 . Ca 2+ -independent activation of calpain can be mediated by neurotrophins 187 , and calpain targeting of the K + /Cl  co-transporter KCC2 has been recently reported 188 , indicating that multiple modes of activity-dependent regulation of neuronal networks and gephyrin availability exist.…”

Section: Box 2 Post-translational Modifications Of Gephyrinmentioning

confidence: 99%

Gephyrin: a master regulator of neuronal function?

2014

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The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligandgated chloride channels-namely, type A GABA (GABA(A)) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission. Shiva Tyagarajan graduated as a molecular virologist at the Pennsylvania State University (USA) and later trained as a neurobiologist during his post-doctoral studies at the University of Zurich. He is currently a group leader and the research focus of his group is to elucidate molecular and cellular mechanisms that couple transcriptional and post-transcriptional programs to regulate GABAergic synaptic plasticity. 3 AbstractThe neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated Cl  channels, namely the GABA A and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that gephyrin postsynaptic clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, posttranslational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses, by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules.Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.On-line summary  Gephyrin is a multi-functional protein, responsible for Moco biosynthesis in all organisms, and for postsynaptic clustering of glycine receptors and GABAA receptors in vertebrate CNS  Gephyrin forms a protein scaffold by self-assembly from trimeric complexes, which interacts with numerous, structurally different proteins, in order to form a high ordered signalling complex in glycinergic and GABAergic synapses  Gephyrin function as a scaffolding protein is regulated by alternate mRNA splicing and by multiple post-transcriptional and posttranslational modifications, which only begin to be understood.  Regulation of gephyrin scaffold by multiple signallin...

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Section: Box 2 Post-translational Modifications Of Gephyrinmentioning

confidence: 99%

Gephyrin: a master regulator of neuronal function?

2014

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“…2011; Puskarjov et al . 2012). It is unlikely that the neuromodulatory enhancement of KCC2 function by mGluRs could overcome the NMDAR‐mediated decrease in KCC2 that occurs during pathophysiological states.…”

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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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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“…Despite the lack of changes in NKCC1, it should be noted that the relative ratio of NKCC1 to KCC2 will have increased compared with the control tissue, thus affecting appropriate GABAergic inhibition. The downregulation of KCC2 takes place rapidly and is likely to be due to calpain-mediated cleavage of the protein (Puskarjov et al, 2012). Electrophysiological recordings demonstrate almost a complete loss of KCC2-mediated Cl -efflux, and suggest changes at the level of transcription found by others (Rivera et al, 2002) are responsible for long-lasting changes in KCC2 function.…”

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confidence: 92%