Molecular Mechanisms Contributing to TARP Regulation of Channel Conductance and Polyamine Block of Calcium-Permeable AMPA Receptors

Soto, David; Coombs, Ian D.; Gratacòs-Batlle, Esther; Farrant, M; Cull-Candy, SG

doi:10.1523/jneurosci.0383-14.2014

Cited by 44 publications

(46 citation statements)

References 40 publications

(28 reference statements)

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“…The proximal end of the C‐terminal region of the TARP, γ‐2 or stargazin, has been shown to attenuate polyamine block of AMPARs through a mechanism that involves a direct interaction with the intracellular domain of GluA1 or GluA4 subunits (Soto et al . ). A similar finding has been reported with Neto2, where positive residues in the proximal intracellular C‐terminal domain are implicated in reducing polyamine block (Fisher & Mott, ).…”

Section: Discussionmentioning

confidence: 97%

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

Brown

Aurousseau

Musgaard

et al. 2016

The Journal of Physiology

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Key points Kainate receptor heteromerization and auxiliary subunits, Neto1 and Neto2, attenuate polyamine ion‐channel block by facilitating blocker permeation.Relief of polyamine block in GluK2/GluK5 heteromers results from a key proline residue that produces architectural changes in the channel pore α‐helical region.Auxiliary subunits exert an additive effect to heteromerization, and thus relief of polyamine block is due to a different mechanism.Our findings have broad implications for work on polyamine block of other cation‐selective ion channels. AbstractChannel block and permeation by cytoplasmic polyamines is a common feature of many cation‐selective ion channels. Although the channel block mechanism has been studied extensively, polyamine permeation has been considered less significant as it occurs at extreme positive membrane potentials. Here, we show that kainate receptor (KAR) heteromerization and association with auxiliary proteins, Neto1 and Neto2, attenuate polyamine block by enhancing blocker permeation. Consequently, polyamine permeation and unblock occur at more negative and physiologically relevant membrane potentials. In GluK2/GluK5 heteromers, enhanced permeation is due to a single proline residue in GluK5 that alters the dynamics of the α‐helical region of the selectivity filter. The effect of auxiliary proteins is additive, and therefore the structural basis of polyamine permeation and unblock is through a different mechanism. As native receptors are thought to assemble as heteromers in complex with auxiliary proteins, our data identify an unappreciated impact of polyamine permeation in shaping the signalling properties of neuronal KARs and point to a structural mechanism that may be shared amongst other cation‐selective ion channels.

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Section: Discussionmentioning

confidence: 97%

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

Brown

Aurousseau

Musgaard

et al. 2016

The Journal of Physiology

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“…In mammals, stargazin is known to alter the number of functional AMPA receptors at a synapse (Chen et al, ; Tomita et al, ; Bats et al, ; Milstein and Nicoll, ; Jackson and Nicoll, ; Matsuda et al, ; Studniarczyk et al, ; Soto et al, ). To examine this we first evaluated the mEPSC amplitude by binning the amplitudes and plotting their distribution as shown in [Fig.…”

Section: Resultsmentioning

confidence: 99%

Zebrafish TARP Cacng2 is required for the expression and normal development of AMPA receptors at excitatory synapses

Roy

Ahmed

Cunningham

et al. 2015

Developmental Neurobiology

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Fast excitatory synaptic transmission in the CNS is mediated by the neurotransmitter glutamate, binding to and activating AMPA receptors (AMPARs). AMPARs are known to interact with auxiliary proteins that modulate their behavior. One such family of proteins is the transmembrane AMPA receptor-related proteins, known as TARPs. Little is known about the role of TARPs during development, or about their function in non-mammalian organisms. Here we report the presence of TARPs, specifically the prototypical TARP, stargazin, in developing zebrafish. We find that zebrafish express two forms of stargazin, Cacng2a and Cacng2b from as early as 12-h post fertilization (hpf). Knockdown of Cacng2a and Cacng2b via splice-blocking morpholinos resulted in embryos that exhibited deficits in C-start escape responses, showing reduced C-bend angles, smaller tail velocities and aberrant C-bend turning directions. Injection of the morphants with Cacng2a or 2b mRNA rescued the morphological phenotype and the synaptic deficits. To investigate the effect of reduced Cacng2a and 2b levels on synaptic physiology, we performed whole cell patch clamp recordings of AMPA mEPSCs from zebrafish Mauthner cells. Knockdown of Cacng2a results in reduced AMPA currents and lower mEPSC frequencies, whereas knockdown of Cacng2b displayed no significant change in mEPSC amplitude or frequency. Non-stationary fluctuation analysis confirmed a reduction in the number of active synaptic receptors in the Cacng2a but not in the Cacng2b morphants. Together, these results suggest that Cacng2a is required for normal trafficking and function of synaptic AMPARs, while Cacng2b is largely non-functional with respect to the development of AMPA synaptic transmission.

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“…This family of proteins includes several members, and namely γ-3, -4, -5, -7, -8 [96,97] , varying in their influence on AMPAR characteristics and manifesting different, although partially overlapping, distribution patterns throughout the CNS. Native AMPARs are thought to be composed of one to four TARPs together with their core pore-forming subunits; however, it is commonly accepted that only one type of TARP is expressed within a specific AMPAR complex [98][99] . TARP assembling influences various fundamental aspects of AMPAR activities thus modifying the neuronal trafficking abilities of GluR2-containing AMPARs.…”

Section: Potential Targets (And Future Perspectives) For the Treatmenmentioning

confidence: 99%

“…TARP assembling influences various fundamental aspects of AMPAR activities thus modifying the neuronal trafficking abilities of GluR2-containing AMPARs. In particular it has been shown that TARPs are engaged in the subunit-specific trafficking of AMPARs, which by modulating the expression of specific AMPAR complexes [99] together with augmented single channel conductance and impaired block of GluR2-lacking AMPARs by endogenous intracellular polyamines tend to increment the molecular complexity operating during stress-related neuronal disorders [98] .…”

Section: Potential Targets (And Future Perspectives) For the Treatmenmentioning

confidence: 99%

AMPAergic mechanisms linked to cerebral ischemia

Mele

Alò

Avolio

et al. 2015

Ther Targets Neurol Dis

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Brain ischemia is the most common cause of invalidity in adults and consequently of death throughout the world. This phenomenon occurs when blood flow is reduced or interrupted in the various brain districts leading to oxygen and glucose deprivation (OGD), which by triggering an intricate succession of biochemical plus molecular events such as an increased production of oxidized and misfolded proteins together with the breakdown of cellular integrity lead to cell death. Despite the lack of information on the triggering mechanisms of ischemic insults, numerous studies are pointing to excitotoxic glutamatergic receptor (GluR) neuronal signaling processes as key mediators of these events. Indeed, from cultured neurons of OGD-related global cerebral ischemia, it seems that this protocol causes a rapid internalization of α amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) thereby suggesting these receptor subtypes as critical components of neuronal death. In particular it seems that OGD-dependent neuronal ischemia occurs via GluR2-sites in which a switching from GluR2-containing Ca 2+-impermeable receptors to GluR2-lacking Ca 2+ -permeable subtypes constitutes an important step. Interestingly attention regarding excitotoxicity-related ischemic events, aside being largely directed to the over activation of AMPARs, appears to be also focused on the activation of the caspase factors through the translocation of the pro-apoptotic B cell lymphoma 2-associated X protein (Bax) to the mitochondria. Although molecular brain mechanisms capable of repairing part of the neuronal damages and to restore the morpho-functional organization during ischemic episodes are well known, this disorder continues to attract much attention especially due to its elevated mortality feature. In this review we analyzed the role played by GluR2 AMPAR subunit in the pathological processes that lead to neurodegenerative diseases with great attention being paid to the assembly of the major synaptic AMPARs together with cellular events that feasibly account for ischemic brain damages. In this context, knowledge of the different molecular mechanisms operating under these conditions may surely provide helpful indications regarding the identification of new therapeutic targets for treating cerebral ischemia.

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Molecular Mechanisms Contributing to TARP Regulation of Channel Conductance and Polyamine Block of Calcium-Permeable AMPA Receptors

Cited by 44 publications

References 40 publications

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

Zebrafish TARP Cacng2 is required for the expression and normal development of AMPA receptors at excitatory synapses

AMPAergic mechanisms linked to cerebral ischemia

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