PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity

Abstract

Central neural plasticity plays a key role in pain hypersensitivity. This process is modulated by brain-derived neurotrophic factor (BDNF) and also involves the type 1a acid-sensing ion channel (ASIC1a). However, the interactions between the BDNF receptor, tropomyosinrelated kinase B (TrkB), and ASIC1a are unclear. Here, we show that deletion of ASIC1 gene suppressed the sustained mechanical hyperalgesia induced by intrathecal BDNF application in mice. In both rat spinal dorsal horn neurons and heterologous cell cultures, the BDNF/TrkB pathway enhanced ASIC1a currents via phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) cascade and phosphorylation of cytoplasmic residue Ser-25 of ASIC1a, resulting in enhanced forward trafficking and increased surface expression. Moreover, in both rats and mice, this enhanced ASIC1a activity was required for BDNF-mediated hypersensitivity of spinal dorsal horn nociceptive neurons and central mechanical hyperalgesia, a process that was abolished by intrathecal application of a peptide representing the N-terminal region of ASIC1a encompassing Ser-25. Thus, our results reveal a novel mechanism underlying central sensitization and pain hypersensitivity, and reinforce the critical role of ASIC1a channels in these processes.

Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death

“…ASIC1a was found to be present in all fractions in which the mitochondrial proteins VDAC and Cyt C were enriched (Figure 4a). Consistent with previous findings, 8,28 we noticed that ASIC1a was also present in the endoplasmic reticulum (ER) fractions, indicated by the enrichment of protein disulfide isomerase (PDI) (Figure 4a). …”

“…Recent evidence suggested an intracellular perinuclear location of ASIC1a in both transfected Chinese hamster ovary (CHO) cells and cultured mouse cortical neurons. 8,28 The association between ASIC1a and ANT suggested that some intracellular ASIC1a proteins might be localized to mitochondria. To verify the mitochondrial localization of ASIC1a, we first made crude cellular fractionations from mouse cortices by sucrose gradient centrifugation at different speeds.…”

“…1 Homomeric ASIC1a channels are expressed throughout central and peripheral nervous systems and are implicated in learning/memory, pain sensation and neuronal death. [1][2][3][4][5][6][7][8] Among all these functions, mediating ischemic neuronal death was one of the most prominent pathological features of ASIC1a channels. [5][6][7] Although it has been established that severe extracellular acidosis in ischemic brain overactivated ASIC1a and caused neuronal death, 5,6 the death mechanisms remained largely unknown particularly considering that ASIC1a channels completely desensitize within a few seconds during persistent acidosis.…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…BDNF increased ASIC1a cell surface expression by inducing phosphorylation of the N-terminal residue Ser25 via the phosphoinositide 3-kinase-protein kinase B cascade. Intrathecal injection of BDNF induced mechanical hyperalgesia, which was prevented by ASIC1a disruption (Duan et al, 2012).…”

“…Administration to the CNS of the spider toxin PcTx1, a specific inhibitor of ASIC1a, diminished pain behavior, further demonstrating the important role of central ASIC1a in pain sensation (Duan et al, 2007;Mazzuca et al, 2007). A recent study showed that ASIC1a in the spinal cord is the target of brain-derived neurotrophic factor (BDNF) (Duan et al, 2012). BDNF increased ASIC1a cell surface expression by inducing phosphorylation of the N-terminal residue Ser25 via the phosphoinositide 3-kinase-protein kinase B cascade.…”