Breaking binary rules for GluA2-containing AMPA receptors in calcium transport

McGill University researchers have demonstrated that AMPA receptors (AMPARs), which mediate fast excitatory neurotransmission in the brain fundamental to learning and memory processes, exhibit varying degrees of calcium permeability depending on their subunit composition.

AMPARs are made up of different subunits, including GluA1, GluA2, GluA3, and GluA4, which determine their functional properties. Findings suggest a broader role for AMPARs in calcium transport, influenced by auxiliary subunits and structural modifications.

GluA2, one of the primary subunits of AMPARs, has long been thought to prevent calcium permeability when included in the receptor complex. Results indicate that the R607E and R607G missense mutations in the GluA2 subunit modify calcium permeability. These mutations have previously been linked to neurodevelopmental disorders, including autism and intellectual disability.

Traditional models categorize AMPARs into two types based on their calcium permeability: GluA2-lacking AMPARs, which transport calcium, and GluA2-containing AMPARs, which were believed to be calcium-impermeable due to RNA editing at the Q/R site. This editing replaces a glutamine (Q) with a positively charged arginine (R), blocking calcium permeability.

Previous research has shown that auxiliary proteins influence AMPAR function, affecting ion permeability and synaptic localization. These studies suggest that AMPARs may not fit strictly into a binary classification of calcium-permeable or calcium-impermeable receptors.

In the study, “GluA2-containing AMPA receptors form a continuum of Ca²⁺-permeable channels,” published in Nature, researchers used electrophysiology and calcium imaging techniques to analyze the calcium permeability of AMPARs under different subunit and auxiliary protein configurations.

Recombinant expression systems were used to reconstruct AMPARs with various auxiliary subunits to mimic their natural assembly in the brain. This approach allowed precise control over subunit composition.

Calcium permeability was assessed by measuring the reversal potential of ion currents in solutions with differing ionic compositions. Whole-cell recordings and outside-out patch-clamp techniques were employed to analyze ion transport properties.

GluA2-containing AMPARs exhibited a range of calcium permeability levels, demonstrating that they do not function as strictly calcium-impermeable receptors. Auxiliary protein type and placement significantly influenced calcium transport. TARPs, particularly TARP-γ2 and TARP-γ8, modified calcium permeability, while CNIH proteins, particularly CNIH-3, had a more pronounced effect.

An extracellular calcium-binding site, identified as Site-G, was found to contribute to calcium permeation. This site, located outside the membrane electric field, facilitates calcium entry into the receptor pore. Findings indicate that AMPARs operate along a continuum of calcium permeability rather than conforming to a rigid binary classification.

Results demonstrate that receptor classification based solely on GluA2 presence does not fully capture their physiological diversity. Data support prior research suggesting that AMPARs do not fit strictly into the previously assumed binary classification of calcium-permeable or calcium-impermeable receptors.

Missense mutations in the GluA2 subunit, such as R607E and R607G, significantly increased calcium permeability. These mutations, associated with autism and intellectual disability, altered receptor function and modified the receptor’s ability to block larger molecules, such as polyamines.

The findings reveal a broader role for GluA2-containing AMPARs in calcium transport, indicating that their function extends beyond previous considerations. Calcium signaling through these receptors may have implications for neuronal communication and synaptic plasticity.

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