AMPAR Regulation in Synaptic Plasticity: The Roles of Calcineurin, CK2, and α2δ-1

AMPA receptors (AMPARs) are ionotropic glutamate receptors that mediate most excitatory transmission in the brain, and they play a key role in synaptic plasticity. Most AMPARs in the brain are permeable to Na+ and K+, but not to calcium ions. However, some are calcium permeable, and these calcium-permeable AMPARs (CP-AMPARs) are important for homeostatic synaptic plasticity as more are produced in response to activity deprivation (Man, 2011). CP-AMPARs have also been implicated in long-term potentiation (Anggono and Huganir, 2012) and in pain. Whether a given AMPAR is calcium permeable depends on its subunit composition. AMPARs are tetramers of different combinations of subunits GluA1–4 (Anggono and Huganir, 2012). In general, GluA2-containing AMPARs are calcium impermeable (CI-AMPARs), whereas GluA2-lacking AMPARs, such as GluA1 homomers, are permeable to calcium. Disruption in the normal balance of CP- versus CI-AMPAR expression in the spinal cord may contribute to various forms of pain. For example, peripheral nerve injury increases levels of GluA2-lacking AMPARs in the spinal cord (Chen et al., 2013). This occurs because the phospho-binding protein α2δ-1 disrupts the assembly of GluA1/GluA2 heteromers (Li et al., 2021). A study recently published in The Journal of Neuroscience (Huang et al., 2024) suggests that the interaction between α2δ-1 and GluA1/GluA2 is regulated by the serine/threonine protein phosphatase calcineurin. Huang et al. (2024) chose to focus on calcineurin because it regulates trafficking of AMPARs to mediate synaptic scaling (Kim and Ziff, 2014). Moreover, calcineurin inhibitors can cause severe neuropathic pain. In fact, calcineurin inhibitor-induced pain syndrome is … Correspondence should be addressed to Richard Coca at richcoca{at}bu.edu.