The mechanosensitive ion channel ASIC2 mediates both proprioceptive sensing and spinal alignment

Abstract

New Findings What is the central question of this study? Proprioception is initiated by mechanosensitive neurons. However, the identities of the molecular players that mediate proprioceptive sensing are largely unknown. Here, we aimed to identify potential mechanosensitive ion channels that mediate proprioceptive signalling. What is the main finding and its importance? We identify the mechanosensitive ion channel ASIC2 as a key component in proprioceptive sensing and a regulator of spine alignment. AbstractBy translating mechanical forces into molecular signals, proprioceptive neurons provide the CNS with information on muscle length and tension, which is necessary to control posture and movement. However, the identities of the molecular players that mediate proprioceptive sensing are largely unknown. Here, we confirm the expression of the mechanosensitive ion channel ASIC2 in proprioceptive sensory neurons. By combining in vivo proprioception‐related functional tests with ex vivo electrophysiological analyses of muscle spindles, we showed that mice lacking Asic2 display impairments in muscle spindle responses to stretch and motor coordination tasks. Finally, analysis of skeletons of Asic2 loss‐of‐function mice revealed a specific effect on spinal alignment. Overall, we identify ASIC2 as a key component in proprioceptive sensing and a regulator of spine alignment.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

“…It is noteworthy that ASIC2 ion channels are present on proprioceptive Type Ia afferent terminals [ 48 ]. The ablation of ASIC2 will result in altered-muscle-spindle-derived stretch responses and motor coordination, in addition to impairment to spinal alignment [ 49 ]. This paper proposed that Piezo2 is needed for mechanostransductory signaling on proprioceptive neurons and ASIC2 modulates this signaling [ 49 ].…”

“…The ablation of ASIC2 will result in altered-muscle-spindle-derived stretch responses and motor coordination, in addition to impairment to spinal alignment [ 49 ]. This paper proposed that Piezo2 is needed for mechanostransductory signaling on proprioceptive neurons and ASIC2 modulates this signaling [ 49 ]. In support, a loss of function on Piezo2 also causes impaired proprioception [ 50 ] and scoliosis [ 51 ].…”

Genetic exploration of roles of acid‐sensing ion channel subtypes in neurosensory mechanotransduction including proprioception

“…Another scRNA‐seq study of proprioceptors showed that ASIC1 and ASIC2 were close to the afferent endings of both MS and GTO (Oliver et al., 2021 ). A recent study showed that ASIC2‐knockout mice exhibited skeletal malalignment and impaired proprioceptive performance in beam‐walking tasks and gait coordination, whereas the morphology of MS and GTO, locomotion abilities and treadmill walking distance were similar to that for wild‐type mice (Bornstein et al., 2023 ). However, the role of ASIC1 in proprioception remains to be determined.…”

Experimental Physiology special issue: ‘Mechanotransduction, muscle spindles and proprioception’

“…For example, using substrate deformation‐driven neurite stretch and micropipette‐guided ultrasound in knockout mouse models of ASIC subtypes, researchers in Chih‐Cheng Chen's laboratory analysed the roles of ASIC3 and ASIC1a in muscle spindles and other organs relying on mechanotransduction (Lin et al., 2024 ). Using in vivo proprioception‐related behavioural assays and ex vivo electrophysiological analyses of muscle spindles, mice lacking ASIC2 were shown to display impairments in muscle spindle responses to stretch and motor coordination tasks, demonstrating that ASIC2s are required for normal muscle spindle function (Bornstein, Watkins et al., 2024 ). Moreover, these mice also revealed skeletal deficits, including an impaired spinal alignment (Bornstein, Watkins et al., 2024 ), further supporting the important role of proprioception for the development or maintenance of the skeletal system.…”

“…Using in vivo proprioception‐related behavioural assays and ex vivo electrophysiological analyses of muscle spindles, mice lacking ASIC2 were shown to display impairments in muscle spindle responses to stretch and motor coordination tasks, demonstrating that ASIC2s are required for normal muscle spindle function (Bornstein, Watkins et al., 2024 ). Moreover, these mice also revealed skeletal deficits, including an impaired spinal alignment (Bornstein, Watkins et al., 2024 ), further supporting the important role of proprioception for the development or maintenance of the skeletal system. Collectively, these studies identify ASICs as key components in mechanosensation.…”