Neurosensory mechanotransduction through acid-sensing ion channels

Abstract

Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels responding to extracellular acidification. ASIC proteins have two transmembrane domains and a large extracellular domain. The molecular topology of ASICs is similar to that of the mechanosensory abnormality 4- or 10-proteins expressed in touch receptor neurons and involved in neurosensory mechanotransduction in nematodes. The ASIC proteins are involved in neurosensory mechanotransduction in mammals. The ASIC isoforms are expressed in Merkel cell-neurite complexes, periodontal Ruffini endings and specialized nerve terminals of skin and muscle spindles, so they might participate in mechanosensation. In knockout mouse models, lacking an ASIC isoform produces defects in neurosensory mechanotransduction of tissue such as skin, stomach, colon, aortic arch, venoatrial junction and cochlea. The ASICs are thus implicated in touch, pain, digestive function, baroreception, blood volume control and hearing. However, the role of ASICs in mechanotransduction is still controversial, because we lack evidence that the channels are mechanically sensitive when expressed in heterologous cells. Thus, ASIC channels alone are not sufficient to reconstruct the path of transducing molecules of mechanically activated channels. The mechanotransducers associated with ASICs need further elucidation. In this review, we discuss the expression of ASICs in sensory afferents of mechanoreceptors, findings of knockout studies, technical issues concerning studies of neurosensory mechanotransduction and possible missing links. Also we propose a molecular model and a new approach to disclose the molecular mechanism underlying the neurosensory mechanotransduction.

Fig. 1

Acid-sensing ion channel (ASIC) proteins reside in nerve endings of mechanoreceptors. ASIC immunoreactivity or ASIC-like currents are found in most sensory mechanoreceptors of trigeminal, nodose and dorsal root ganglia. ASIC-expressing mechanoreceptors have diverse sensory functions ranging from nociception, touch, proprioception and baroreception, to visceral mechanosensation.

Fig. 2

Probing sensory nerve mechanotransduction via localized elastomeric matrix control. Mechanical stretching imposed on a neurite via surface-modified elastomeric matrices. To probe the extracellular matrix (ECM)-tethered mechanotransduction on nerve terminals, neurite-bearing dorsal root ganglia neurons are cultured on an ECM-coated polydimethylsiloxane substrate that mimics a physiologically relevant elastic modulus (10–100 kPa). We can use whole-cell patch clamp recording to measure the electrical responses of neurosensory mechanotransduction on a single neurite by substrate indentation at a location adjacent to the neurite, which will deform the substrate and thus stretch the neurite without contacting it. This figure was modified from [82].

Fig. 3

Schematic model of the ASIC complex in mediating mechanotransduction on sensory afferents. From the concepts of Chalfie (2009), we propose a tether model for the stretch-activated ion channel in the mammalian sensory nerve. Proteins that are needed in neurosensory mechanotransduction include the stretch-activated ion channel (e.g. ASIC3), ECM (collagens) and ECM-linker proteins (matrilin-2), intracellular linker proteins (e.g. stomatin-domain protein stomatin-like protein-3 [SLP-3], and cytoskeleton proteins (actin filament and microtubule). Integrin/syndecan-4 signalling may act in parallel to open another mechanically activated channel (MA) or modulate the ASIC complex.