Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Abstract

TASK3 (TWIK-related acid-sensitive K 1 channel 3) potassium channels are members of the two-pore-domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted, and a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiologic recordings, we have found that, although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared with wild-type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators, such as extracellular acidification, extracellular zinc, and activation of Gaq-coupled muscarinic (M3) receptors, compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain-of-function additional mutation of TASK3 channels (A237T) or by application of the nonsteroidal anti-inflammatory drug flufenamic acid (FFA; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid). FFA produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacologic enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

“…By contrast, FFA has relatively little effect on the related K2P channel TASK3 (Veale et al, 2014). The relative effectiveness of FFA, MFA, and NFA on TREK1 is consistent with that found previously by Takahira et al (2005).…”

Aristolochic acid, a plant extract used in the treatment of pain and linked to Balkan endemic nephropathy, is a regulator of K2P channels

“…We next considered whether activators of TASK‐2 channels might induce current through T108P mutated channels, as has been seen previously for other non‐functional or reduced‐function, mutated K2P channels (Ma et al , ; Veale et al , ). Changes in external pH are known to regulate TASK‐2 channels (Reyes et al , ).…”

“…FFA (100 μM) is a known enhancer of several K2P channels (Veale et al , ; see also Figure ). We showed that this compound is also able to enhance current through both WT TASK‐2 channels (Figure A and B) and TASK‐2_T108C channels (Figure C and D).…”

“…For the step component of the protocol, cells were hyperpolarized from a holding voltage of −60 to −80 mV for 100 ms then stepped to −40 mV for 500 ms. For the ramp, cells were then stepped to −120 mV for 100 ms, followed by a 500 ms voltage ramp to +20 mV and a step back to −80 mV for another 100 ms, before being returned to the holding voltage of −60 mV. This protocol was composed of sweeps that lasted 1.5 s (including sampling at the holding voltage) and was repeated once every 5 s (see also Veale et al , ).…”

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

“…23,45 In this homodimeric conformation the channel is poorly functioning, with low current levels, which are inwardly rectifying and show altered potassium selectivity. 46 When G236 is mutated to an aspartate, however, the current is significantly increased through these channels, remains outwardly rectifying and potassium selective.…”