Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation

Brown, Patricia M.G.E.; McGuire, Hugo; Bowie, Derek

doi:10.1085/jgp.201711895

Cited by 25 publications

(50 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Supporting the importance of the selectivity filter for anchoring polyamines in iGluR is the reduction of channel block by endogenous polyamines caused by substitutions in the filter (Panchenko et al, 2001; Wilding et al, 2010). Block by endogenous polyamines is attenuated by STZ and other TARPs, suggesting that the TARP-stabilized, maximally-conducting CP-AMPAR ion channel confirmation (Twomey et al, 2017a) allows for faster relief of trapped endogenous polyamines (Brown et al, 2018; Jackson et al, 2011; Soto et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Twomey

Yelshanskaya

Vassilevski

et al. 2018

Neuron

View full text Add to dashboard Cite

AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Twomey

Yelshanskaya

Vassilevski

et al. 2018

Neuron

View full text Add to dashboard Cite

show abstract

“…The AMPAR ion channel is lined by both M3 and M2, with the selectivity filter formed by the extended, nonhelical region of M2. Since the selectivity filter coordinates polyamines and polyamine toxin tails (Twomey et al, 2018), the TM4–M2 interactions could be the reason why TARPs increase polyamine permeation through AMPARs and attenuate polyamine block (Soto et al, 2007; Jackson et al, 2011; Brown et al, 2018). The AMPAR–TARP TMD interface, while overall similar, is unique per TARP subunit.…”

Section: Interfaces Between Ampars and Tarpsmentioning

confidence: 99%

Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes

Twomey

Yelshanskaya

Sobolevsky

2019

Journal of General Physiology

View full text Add to dashboard Cite

Fast excitatory neurotransmission is mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (AMPAR). AMPARs initiate depolarization of the postsynaptic neuron by allowing cations to enter through their ion channel pores in response to binding of the neurotransmitter glutamate. AMPAR function is dramatically affected by auxiliary subunits, which are regulatory proteins that form various complexes with AMPARs throughout the brain. The most well-studied auxiliary subunits are the transmembrane AMPAR regulatory proteins (TARPs), which alter the assembly, trafficking, localization, kinetics, and pharmacology of AMPARs. Recent structural and functional studies of TARPs and the TARP-fold germ cell-specific gene 1-like (GSG1L) subunit have provided important glimpses into how auxiliary subunits regulate the function of synaptic complexes. In this review, we put these recent structures in the context of new functional findings in order to gain insight into the determinants of AMPAR regulation by TARPs. We thus reveal why TARPs display a broad range of effects despite their conserved modular architecture.

show abstract

“…Interaction with CNIHs also reduce CP-AMPARs desensitization and polyamine sensitivity. Resent findings suggest that both TARPs and CNIHs relieve channel block by enhancing the rate of blocker permeation ( Brown et al, 2018 ). Similarly, to type 1 TARPs and CNIHs, GSG1L slows deactivation and desensitization of CP-AMPARs ( Shanks et al, 2012 ).…”

Section: Factors That Can Influence the Contribution Of Polyamine Depmentioning

confidence: 99%

The Role of Polyamine-Dependent Facilitation of Calcium Permeable AMPARs in Short-Term Synaptic Enhancement

Rozov

Zakharova

Vazetdinova

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Depending on subunit composition AMPA receptor channels can be subdivided into two groups: GluA2-containing calcium impermeable AMPARs, and GluA2-lacking calcium permeable, AMPARs. These two groups differ in a number of biophysical properties and, most likely, in their functional role at glutamatergic synapses. GluA2-lacking channels have received a lot of attention over the last two decades mainly due to high calcium permeability, which was suggested to play a significant role in the induction of long-term synaptic plasticity in healthy tissue and neuronal death under neuropathological conditions. However, calcium permeable AMPARs possess another property that can contribute substantially to frequency dependent dynamics of synaptic efficacy. In the closed state calcium permeable AMPARs are blocked by endogenous polyamines, however, repetitive activation leads to progressive relief from the block and to the facilitation of ion flux through these channels. Polyamine-dependent facilitation of AMPARs can contribute to short-term plasticity at synapses that have high initial release probability and express calcium permeable AMPARs. During synaptic transmission activity-dependent relief from polyamine block of postsynaptic calcium-permeable AMPARs either counteracts presynaptic short-term depression in a frequency-dependent manner or, under specific stimulation conditions, induces facilitation of a synaptic response. Taking into account the fact that expression of calcium permeable AMPARs is developmentally regulated, depends on network activity and increases in diseased brain states, polyamine-dependent facilitation of calcium permeable AMPARs is an important, entirely postsynaptic mechanism of synaptic gain regulation.

show abstract

Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation

Cited by 25 publications

References 51 publications

Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors

Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes

The Role of Polyamine-Dependent Facilitation of Calcium Permeable AMPARs in Short-Term Synaptic Enhancement

Contact Info

Product

Resources

About