Tandem pore domain acid-sensitive K channel 3 (TASK-3) regulates visual sensitivity in healthy and aging retina

Abstract

Retinal ganglion cells (RGCs) not only collect but also integrate visual signals and send them from the retina to the brain. The mechanisms underlying the RGC integration of synaptic activity within retinal circuits have not been fully explored. Here, we identified a pronounced expression of tandem pore domain acid-sensitive potassium channel 3 (TASK-3), a two–pore domain potassium channel (K2P), in RGCs. By using a specific antagonist and TASK-3 knockout mice, we found that TASK-3 regulates the intrinsic excitability and the light sensitivity of RGCs by sensing neuronal activity–dependent extracellular acidification. In vivo, the blockade or loss of TASK-3 dampened pupillary light reflex, visual acuity, and contrast sensitivity. Furthermore, overexpressing TASK-3 specifically in RGCs using an adeno-associated virus approach restored the visual function of TASK-3 knockout mice and aged mice where the expression and function of TASK-3 were reduced. Thus, our results provide evidence that implicates a critical role of K2P in visual processing in the retina.

Development of covalent chemogenetic K2Pchannel activators

“…Leak potassium currents produced by K 2P channels play a fundamental role in membrane potential stabilization and cellular excitability regulation 1,2 . Consequently, K 2P s are important to normal and pathophysiological processes 2,3 such as action potential propagation 4,5 , pain 6-8 , sleep 9 , intraocular pressure 10 , retinal visual processing 11 , migraine 12 , depression 13 , pulmonary hypertension 14 , and sleep apnea 15 . Because of their strong effects on cellular excitability, K 2P s are highly regulated by a variety of physiological cues and regulatory pathways 2 .…”

Retinal Mechanical Sensation

“…Using immunocytochemistry, patchclamp, PCR, and western blot, Zhang and colleagues [210] found that rd1 mice express higher levels of the mRNA and protein of TREK1 and TRAAK, and the arachidonic acid-evoked current was bigger in RGCs. TASK-3 also showed some regulation on the excitability of mouse RGCs [211]. The data suggest that K2Ps have physiological and pathological roles in RGCs.…”

Inhibition of high-voltage-activated calcium currents by acute hypoxia in cultured retinal ganglion cells

“…It has been shown that ROS produced by RGCs' mitochondria modulate ion channel gating and excitability (Smith et al, 2023 ). It is also important to remember that RGCs can directly sense pH changes with TWIK-related acid-sensitive K+ (TASK) channels (Zhong et al, 2013 ; Wen et al, 2022 ) and to consider this in planning the research and interpretation of the results. In our research, we isolated hypoxia-induced effects using such a strong buffer as HEPES to maintain stable pH.…”