Fragile X mental retardation protein controls ion channel expression and activity

Abstract

Fragile X-associated disorders are a family of genetic conditions resulting from the partial or complete loss of fragile X mental retardation protein (FMRP). Among these disorders is fragile X syndrome, the most common cause of inherited intellectual disability and autism. FMRP is an RNA-binding protein involved in the control of local translation, which has pleiotropic effects, in particular on synaptic function. Analysis of the brain FMRP transcriptome has revealed hundreds of potential mRNA targets encoding postsynaptic and presynaptic proteins, including a number of ion channels. FMRP has been confirmed to bind voltage-gated potassium channels (K 3.1 and K 4.2) mRNAs and regulates their expression in somatodendritic compartments of neurons. Recent studies have uncovered a number of additional roles for FMRP besides RNA regulation. FMRP was shown to directly interact with, and modulate, a number of ion channel complexes. The sodium-activated potassium (Slack) channel was the first ion channel shown to directly interact with FMRP; this interaction alters the single-channel properties of the Slack channel. FMRP was also shown to interact with the auxiliary β4 subunit of the calcium-activated potassium (BK) channel; this interaction increases calcium-dependent activation of the BK channel. More recently, FMRP was shown to directly interact with the voltage-gated calcium channel, Ca 2.2, and reduce its trafficking to the plasma membrane. Studies performed on animal models of fragile X syndrome have revealed links between modifications of ion channel activity and changes in neuronal excitability, suggesting that these modifications could contribute to the phenotypes observed in patients with fragile X-associated disorders.

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

“…This is consistent with our patch clamping recordings where we find a significantly reduced proportion of FMRP-deficient neurons that fire multiple action potentials compared with control. Furthermore, a well-known role for FMRP is in the regulation of key proteins involved in synaptic function and neurotransmission [59]. This is corroborated by our transcriptome and proteome analyses where we observed dysregulation of genes involved in neuronal excitability, neurotransmitter secretion, and synaptic transmission such as potassium channels in FMRP-deficient neurons.…”

Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation

“…We speculate that, during neuronal stimulation, the transient influx and transient release of calcium ions stored within the endoplasmic reticulum (88,89) may disrupt protein-RNA and protein-protein interactions within neuronal granules to favor granule disassembly. Moreover, FMRP interacts directly with ion channels and regulates calcium signaling via mechanisms that are not well-understood (42,90). Thus, a potential novel role for the low-complexity region of FMRP is to act as a direct biophysical calcium sensor within a neuronal granule.…”

“…Previously, smaller FMRP protein fragments have been demonstrated to phase separate in vitro (37,38). FMRP is multifunctional and is involved in numerous processes, including pre-mRNA processing (39), neuronal granule transport (40), translational regulation (41), and ion channel binding (42). However, its canonical and best-studied role is to repress translation in a phosphorylation-dependent manner via activity from neuronal G protein-coupled receptors, such as the metabolic glutamate receptor (mGluR) (43).…”

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…FMRP regulates the expression and activity of a substantial number of voltage-gated ion channels (Contractor et al, 2015;Ferron, 2016;Richter et al, 2015). For example, FMRP controls the translation of Kv4.2, Kv3.1, and HCN1 mRNAs encoding K + channels, which control neuronal excitability (Brown et al, 2001;Darnell et al, 2011;Miyashiro et al, 2003).…”