Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

Abstract

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C -mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a/3 Heteromeric Channels

“…ASIC1a is a critical member of the ASICs family and mainly expressed in the brain [ 11 , 16 ]. During the physiological process, ASIC1a is involved in synaptic transmission [ 1 , 33 ], learning and memory [ 11 , 34 ], fear conditioning [ 35 ], and pain modulation [ 36 , 37 ]. For example, ASIC1a channels contribute to both long-term potentiation (LTP) and long-term depression [ 11 , 34 ].…”

Upregulation of spinal ASIC1 by miR‐485 mediates enterodynia in adult offspring rats with prenatal maternal stress

“…Recent studies have also shown that changes in expression and functions of key ion channels and receptors in extrinsic sensory neurons play an important role in the abnormal pain of gastrointestinal diseases 14‐16 . Acid‐sensing ion channels (ASICs) are a class of cation channels that are directly activated by extracellular acids and belong to the degenerate protein, epithelial Na + ion channel superfamily (DEG/ENaC), which are widely distributed in central and peripheral nervous systems 17 . ASICs are divided into at least six isoforms: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4.…”

“…[14][15][16] Acid-sensing ion channels (ASICs) are a class of cation channels that are directly activated by extracellular acids and belong to the degenerate protein, epithelial Na + ion channel superfamily (DEG/ENaC), which are widely distributed in central and peripheral nervous systems. 17 ASICs are divided into at least six isoforms: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4.…”

Postsynaptic Targeting and Mobility of Membrane Surface-Localized hASIC1a

“…Previously, we used a central pain-sensitization model to show that BDNF upregulates the surface expression of ASIC1a in spinal dorsal horn neurons [ 57 ]. Since ASIC1a function has been implicated in synaptic plasticity [ 21 , 25 , 27 , 78 ], we asked whether membrane trafficking of ASIC1a in the dendritic and synaptic surface of cortical neurons responds to strengthening of neuronal or synaptic activity by BDNF. Here, we first showed that BDNF treatment increased the surface expression of endogenous ASIC1a in cultured rat cortical neurons, as revealed by surface biotinylation (Fig.…”