Differential Regulation of BK Channels by Fragile X Mental Retardation Protein

Abstract

are ongoing at two more locations); for an 871 atom (protein, 50 water molecules, and the ion) pore section, quantum calculations optimized (energy minimized) the section, and the energy and ion hydration at each ion position were determined. The protein structures the water column. It appears that hydration may explain the reason for the strong conservation of the threonine at the bottom of the selectivity filter, which interacts with water in a characteristic way, producing a ''basket'' of four water molecules H-bonded to the threonines. One remaining problem is determining how the ion exchanges its own hydration shell to be cosolvated by the four threonine hydroxyl groups, breaking the water ''basket''. Once that is accomplished, the ion can proceed through the selectivity filter. At the entrance to the pore at the bottom of the water column (i.e., the gate), hydration is strongly rearranged when an ion arrives. A small increase in diameter from the closed state, approximately 5 Å , is adequate to admit the ion and hold it by a local increase in the density of the water hydrating it; a wide open gate would often lose the ion back to solution, greatly diminishing the current. The entering ion remains held as the ion above it moves; following this, the gate ion can move up to the center of the pore cavity. Optimizations were done using HF/6-31G*, while energy calculations used B3LYP/6-31G** on the optimized structures.

An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

“…Likewise, cerebellar atropy may represent a consequence of seizures rather than a direct effect of channel dysfunction [48]. BK channel function has been implicated in a range of atypical cognitive phenotypes in animal models that could inform observations from patients [49][50][51][52][53][54][55][56]. Furthermore, BK α expression is upregulated in the late embryonic period and early prenatal period [53,57,58], and this is thought to be linked to functional maturation of affected neuronal populations [59].…”

FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

“…We exploited the ability of FMRP WT to rescue TMR-dextran uptake to perform molecular replacement studies using two loss of function mutants: FMRP I304N - that does not bind ribosomes (De Boulle et al, 1993) and FMRP R138Q - that does not bind BK channels (Myrick et al, 2015; Kshatri et al, 2020) (Fig. 4C).…”

“…However, it also has protein synthesis-independent presynaptic functions, such as mediating ion channel gating, activation, and density (reviewed in Ferron, 2016). For example, FMRP interacts with Slack potassium channels (Brown et al, 2010), N-type calcium channels (Ferron et al, 2014) and large conductance voltage and calcium-gated big potassium (BK) channels (Deng et al, 2013; Deng and Klyachko, 2016; Kshatri et al, 2020). The absence of FMRP at CA3-CA1 hippocampal synapses leads to reduced BK channel activity and excessive AP broadening (Deng et al, 2013; Wang et al, 2014; Deng and Klyachko, 2016), resulting in increased presynaptic calcium influx during high frequency stimulation (Deng et al, 2011; Deng et al, 2013).…”