Acid Sensing Ion Channels in Dorsal Spinal Cord Neurons

Acid-sensing ion channel (ASIC) 1a/2a heteromers have a flexible 2:1/1:2 stoichiometry

“…The coexistence with homomeric ASIC2a was not documented because the most acidic pH tested was 5.0, which will not substantially activate homomeric ASIC2a due to its low H + affinity. Similar to our own results, one study found that functional properties of heteromeric ASIC1a/2a shift depending on the ratio of DNAs transfected into COS cells (32). Based on the similarity of currents at a 2:1 ratio (ASIC1a/ASIC2a) with endogenous currents of spinal horn neurons, it was concluded that heteromeric ASICs in spinal horn neurons have a 2:1 (ASIC1a/ ASIC2a) stoichiometry.…”

“…The ASIC1a/2a heteromer is one of the major ASICs in the brain; the existence of ASIC1a/2a heteromers with two different compositions indicates that the variety of ASICs in the central nervous system might be greater than previously thought. For hippocampal neurons and dorsal horn neurons it has been specifically shown that heteromeric ASIC1a/ 2a channels coexist with homomeric ASIC1a in a large fraction of neurons (3)(4)(5)(6)32). The coexistence with homomeric ASIC2a was not documented because the most acidic pH tested was 5.0, which will not substantially activate homomeric ASIC2a due to its low H + affinity.…”

Acid-Sensing Ion Channels in Neurodegenerative Diseases: Potential Therapeutic Target

“…The electrophysiological properties and pharmacological profiles of ASICs have been extensively explored in heterologous expression systems Hesselager et al, 2004) and in neurons from different brain regions, such as cortex (Varming, 1998;Chu et al, 2004Chu et al, , 2006, hippocampus (Baron et al, 2002;Askwith et al, 2004), striatum (Jiang et al, 2009), cerebellum (Allen & Attwell, 2002), retinal ganglion (Lilley et al, 2004), and spinal cord (Wu et al, 2004;Baron et al, 2008). Fig.…”

“…Each subunit has two transmembrane domains with a large extracellular loop and short intracellular N-and C-termini (Waldmann et al, 1997b). Functional ASICs are trimeric complexes of these subunits (Jasti et al, 2007;Gonzales et al, 2009) and most of these subunits can form homomeric and/or heteromeric channels (Benson et al, 2002;Baron et al, 2002Baron et al, , 2008Wemmie et al, 2002Wemmie et al, , 2003Chu et al, 2004Chu et al, , 2006Xiong et al, 2004;Zha et al, 2006;Sherwood et al, 2011). ASICs are enriched in brain neurons (Alvarez de la Rosa et al, 2003;Wemmie et al, 2003;Xiong et al, 2004;Sherwood et al, 2011), where at least three (ASIC1a, ASIC2a and ASIC2b) of the seven subunits can be found.…”

Ligand-gated Ion Channels

“…The relationship of the cloned ASICs to endogenously expressed proton-gated ion channels is becoming established (Escoubas et al, 2000;Sutherland et al, 2001;Wemmie et al, 2002Wemmie et al, , 2003Wemmie et al, , 2006Diochot et al, 2004Diochot et al, , 2007Lingueglia et al, 2006;Lingueglia, 2007;Hattori et al, 2009). Heterologously expressed heteromultimers form ion channels with altered kinetics, ion selectivity, pH-sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones (Lingueglia et al, 1997;Babinski et al, 2000, Escoubas et al, 2000, Baron et al, 2008. ASIC1a: g~14pS; PNa/PK = 5-13, PNa/PCa = 2.5; rapid activation rate (5.8-13.7 ms) rapid inactivation rate (1.2-4 s) @ pH 6.0, slow recovery (5.3-13 s) @ pH 7.4 ASIC1b: g~19 pS; PNa/Pk = 14.0; PNa >> PCa; rapid activation rate (9.9 ms); rapid inactivation rate (0.9-1.7 s) @ pH 6.0, slow recovery ( Psalmotoxin 1 (PcTx1) inhibits ASIC1a by modifying activation and desensitization by H + , but promotes ASIC1b opening.…”