pH and proton-sensitive receptors in brain ischemia

Abstract

Extracellular proton concentration is at 40 nM when pH is 7.4. In disease conditions such as brain ischemia, proton concentration can reach µM range. To respond to this increase in extracellular proton concentration, the mammalian brain expresses at least three classes of proton receptors. Acid-sensing ion channels (ASICs) are the main neuronal cationic proton receptor. The proton-activated chloride channel (PAC), which is also known as (aka) acid-sensitive outwardly rectifying anion channel (ASOR; TMEM206), mediates acid-induced chloride currents. Besides proton-activated channels, GPR4, GPR65 (aka TDAG8, T-cell death-associated gene 8), and GPR68 (aka OGR1, ovarian cancer G protein-coupled receptor 1) function as proton-sensitive G protein-coupled receptors (GPCRs). Though earlier studies on these GPCRs mainly focus on peripheral cells, we and others have recently provided evidence for their functional importance in brain injury. Specifically, GPR4 shows strong expression in brain endothelium, GPR65 is present in a fraction of microglia, while GPR68 exhibits predominant expression in brain neurons. Here, to get a better view of brain acid signaling and its contribution to ischemic injury, we will review the recent findings regarding the differential contribution of proton-sensitive GPCRs to cerebrovascular function, neuroinflammation, and neuronal injury following acidosis and brain ischemia.

Keywords: Acid signaling; acidosis; brain pH; ischemia; neuroinflammation; neuronal injury.

Figure 1.

pH dynamics and the three classes of acid-sensitive receptors in the brain. (a) Illustration showing brain pH changes during brain ischemia and following reperfusion. The red line illustrates the change in permanent occlusion. The orange line illustrates the approximate change following reperfusion. These curves may shift upward or downward in hypoglycemic or hyperglycemic conditions, respectively. See text for details. (b) Diagram illustrating the pH sensitivity of the three classes of proton receptors. The curves are qualitative representation of the approximate/average pH response curves of a group of receptors within that family. See text for more explanation.

Figure 2.

Summary of the expression, signaling, and impact on ischemic injury of the acid-sensitive receptors. 3D illustration of ASIC and PAC/ASOR was based on crystal structure deposited in NCBI PDB database (PBD ID 3S3W and 7JNA) and created with the NGL viewer.^– Note that these structures do not contain most of the intracellular tails. For GPCRs, the 3D illustrations were generated using GPCR homology modeling located on GPCRdb.^, The signaling illustrates the key pathways which have been either demonstrated or implicated in the receptor’s contribution to neuronal injury, vascular dysfunction, or neuroinflammation.