TASK1 and TASK3 Are Coexpressed With ASIC1 in the Ventrolateral Medulla and Contribute to Central Chemoreception in Rats.

Xia Wang,Linlin Shen,Ruijuan Guan,Nana Song,Danian Zhu,Xiaomei Zhao

doi:10.3389/fncel.2018.00285

Xia Wang, Linlin Shen + Show 4 more

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https://doi.org/10.3389/fncel.2018.00285

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Abstract

The ventrolateral medulla (VLM), including the lateral paragigantocellular nucleus (LPGi) and rostral VLM (RVLM), is commonly considered to be a chemosensitive region. However, the specific mechanism of chemoreception in the VLM remains elusive. Acid-sensing ion channels (ASICs), a family of voltage-independent proton-gated cation channels, can be activated by an external pH decrease to cause Na+ entry and induce neuronal excitability. TWIK-related acid-sensitive potassium channels (TASKs) are members of another group of pH-sensitive channels; in contrast to AISICs, they can be stimulated by pH increases and are inhibited by pH decreases in the physiological range. Our previous study demonstrated that ASICs take part in chemoreception. The aims of this study are to explore whether TASKs participate in the acid sensitivity of neurons in the VLM, thereby cooperating with ASICs. Our research demonstrated that TASKs, including TASK1 and TASK3, are colocalized with ASIC1 in VLM neurons. Blocking TASKs by microinjection of the non-selective TASK antagonist bupivacaine (BUP), specific TASK1 antagonist anandamide (AEA) or specific TASK3 antagonist ruthenium red (RR) into the VLM increased the integrated phrenic nerve discharge (iPND), shortened the inspiratory time (Ti) and enhanced the respiratory drive (iPND/Ti). In addition, microinjection of artificial cerebrospinal fluid (ACSF) at a pH of 7.0 or 6.5 prolonged Ti, increased iPND and enhanced respiratory drive, which were inhibited by the ASIC antagonist amiloride (AMI). By contrast, microinjection of alkaline ACSF decreased iPND and respiratory drive, which were inhibited by AEA. Taken together, our data suggest that TASK1 and TASK3 are coexpressed with ASIC1 in the VLM. Moreover, TASK1 and TASK3 contribute to the central regulation of breathing by coordinating with each other to perceive local pH changes; these results indicate a novel chemosensitive mechanism of the VLM.

Highlights

Central chemoreceptors sense changes of H+ concentration ([H+]) in cerebrospinal fluid (CSF), play an important role in respiratory regulation and contribute to acid-base homeostasis
The slides were incubated with primary antibodies against TASK1 (Alomone Laboratory, Israel, 1:100), TASK3 (Alomone Laboratory, Israel, 1:100) and ASIC1 (Santa Cruz Biotechnology, Dallas, TX, USA, 1:100), Neurofilament-H (Abcam, Cambridge, MA, USA) which were diluted in 0.01 M PBS, overnight
We focused on the role of another class of pH-sensitive ion channels, TASKs, in breathing regulation and their cooperation with acid-sensing ion channels (ASICs) in the central chemosensory system

Summary

Introduction

Central chemoreceptors sense changes of H+ concentration ([H+]) in cerebrospinal fluid (CSF), play an important role in respiratory regulation and contribute to acid-base homeostasis. It has been reported that chemoreceptors exist in many brain areas including raphe, retrotrapezoid nucleus (RTN), ventrolateral medulla (VLM), locus coeruleus (LC) and the nucleus of tractus solitaries (NTS). Among these chemosensitive areas, VLM is considered to specialize in central chemoreception (Millhorn and Eldridge, 1986). Our previous study found that ASIC1 in the VLM contributes to chemoreception and the regulation of respiration (Song et al, 2016). It is unclear whether TASKs participate in central chemoreception

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