Proton production, regulation and pathophysiological roles in the mammalian brain

Abstract

Abstract:The recent demonstration of proton signaling in C. elegans muscle contraction suggests a novel mechanism for proton-based intercellular communication and has stimulated enthusiasm for exploring proton signaling in higher organisms. Emerging evidence indicates that protons are produced and regulated in localized space and time. Furthermore, identification of proton regulators and sensors in the brain leads to the speculation that proton production and regulation may be of major importance for both physiological and pathological functions ranging from nociception to learning and memory. Extracellular protons may play a role in signal transmission by not only acting on adjacent cells but also affecting the cell from which they were released. In this review, we summarize the upstream and downstream pathways of proton production and regulation in the mammalian brain, with special emphasis on the proton extruders and sensors that are critical in the homeostatic regulation of pH, and discuss their potential roles in proton signaling under normal and pathophysiological conditions.

Acid-sensing ion channels in pain and disease

“…However, thus far, postsynaptic ASIC-dependent currents have not been detected during neurotransmission 20,22,38 . Protons generated by other sources, such as localized energy metabolism, might also contribute to ASIC activation 50,51 , as might the growing list of ASIC modulators 10 (TABLE 2). The downstream mechanisms by which ASIC1A activation produces its effects also remain poorly defined.…”

“…A number of neurological diseases involve acidosis, arising from several possible sources, including ischaemia, inflammation, metabolism and synaptic transmission 50 (FIG. 4).…”

Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation

“…Activation of TLRs triggers a cascade of intracellular events leading to activation of several transcription factors, including NF- κ B, activator protein-1 (AP-1), and IFN-regulatory factor-3 (IRF-3) and -7 that regulate the expression of various cytokines and chemokines, responses that are performed in the CNS mainly by mastocytes and microglia. In addition, activation of innate immune responses via TLRs is a prerequisite for the generation of adaptive immune responses [22] that become relevant in autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). …”

“…The number of molecular members that comprise the TLR family is ten in humans (TLRs 1–10) and twelve in mice (TLRs 1–9; TLRs 11–13) [22]. Some TLRs can be expressed on the cell surface (TLRs 1, 2, 4, 5, 6, and 10) or in intracellular compartments (TLRs 3, 7/8, and 9), but others can be found in both the cell membrane and intracellular compartments (TLR3 and TLR7; endosomes and endoplasmic reticulum) [21].…”

“…Each TLR detects distinct PAMPs derived from viruses, bacteria, mycobacteria, fungi, or parasites. For example, TLR3 and TLR7/8 detect ds and single-stranded (ss) RNAs from virus, respectively; TLR4 responds to LPS from Gram-negative bacteria; and TLR9 senses bacterial DNA that contains unmethylated cytosine-guanosine dinucleotides (CpG) [22–25]. …”