Breakthrough in the Senses of Touch and Movement: ASIC3 Identified as a Key Player
Researchers studying the poorly understood mechanical senses of touch and movement have reported a significant advance that could eventually aid people with movement disorders, spinal cord injuries, high blood pressure and help improve the design of robotics and prosthetics.
The mechanical senses—those that convey touch, limb position and movement—are essential to functions such as balance, coordination, hearing-related feedback and blood pressure regulation. Compared with vision, smell, taste, temperature and pain, these senses are less well characterized at the molecular level. New work from teams at the Universities of Aberdeen and Durham, together with collaborators at Academia Sinica in Taiwan, identifies a specific protein, ASIC3, as contributing to the detection of small, rapid movements in nerve endings known as proprioceptors.
The study shows that nerve endings enable us to perceive everything from the faint brush of a breeze across the skin to the position and motion of our limbs. These same endings also influence autonomic processes such as blood pressure and may play a role in reflexive muscle spasms that follow spinal cord injury. By examining how the loss of ASIC3 alters nerve function, researchers were able to link this protein to the fine tuning of dynamic mechanosensation.
When ASIC3 was experimentally deactivated in mice, investigators observed several consistent changes. Very gentle movements were no longer reliably detected by those nerve cells, isolated muscles became more responsive to rapid stimuli, and animals showed reduced precision in placing their feet while walking. These findings indicate that ASIC3 contributes specifically to the detection of small, fast movements—that is, dynamic mechanosensitivity in proprioceptors—rather than to all forms of mechanical sensing.
Previously, the role of ASIC3 in mechanosensation had been disputed. To address this, the team developed more sensitive and systematic experimental approaches, combining genetic models, targeted knockouts, electrophysiology and controlled mechanical stimulation of nerve-bearing tissue. This methodological combination allowed the researchers to measure responses to subtle, substrate-based deformations of neurites and to distinguish those responses from direct indentation of nerve endings.
Dr Guy Bewick of the University of Aberdeen and colleagues emphasize that movement detection is inherently complex: it requires sensing distance, speed, force and smoothness, and may rely on groups of proteins clustered together in functional units within a single nerve ending. The new work helps to disentangle which proteins contribute to which aspects of mechanotransduction, a topic that has been difficult to resolve until now.
The implications of defining protein roles in mechanosensory endings are broad. Knowing which molecules underlie particular mechanosensory properties could make it possible to develop drugs that selectively modify those proteins’ activity. For example, reducing over-sensitivity of specific endings might prevent pathological reflex contractions and pain in people with spinal cord injury or cerebral palsy without producing the generalized weakness caused by some current treatments. Conversely, targeting related channels could offer a route to lower high blood pressure if those channels modulate autonomic reflexes affecting vascular tone.
The study builds on earlier work from Dr Bewick and colleagues, which identified a protein called whirlin as important for clustering mechanosensory proteins together in nerve endings. That prior discovery suggested that functional groups of proteins act together in proprioceptors; the current findings on ASIC3 begin to specify which functions individual components perform within those clusters.
Source: Euan Wemyss – University of Aberdeen
Image credit: Karen Yee, Monell Center.
Original research: The study, titled “Evidence for the involvement of ASIC3 in sensory mechanotransduction in proprioceptors,” reports experiments using Asic3-knockout and knockin mouse models, a floxed Asic3 allele to enable targeted deletion in proprioceptors, localized elastic-matrix movement assays, and electrophysiological recording from dorsal root ganglion neurons. The research documents heterogeneous expression of ASIC3 in sensory neurons and links the loss of ASIC3 to impaired spindle afferent sensitivity to dynamic mechanical stimuli and to deficits in coordinated walking tasks.
Abstract summary
The research establishes that acid-sensing ion channel 3 (ASIC3) is expressed in parvalbumin-positive proprioceptor axons that innervate muscle spindles and that targeted deletion of Asic3 impairs mechanotransduction driven by substrate deformation-induced neurite stretching. Global and proprioceptor-specific knockouts displayed consistent deficits in dynamic mechanosensitivity and in behavioral tasks requiring precise foot placement and balance. These data support ASIC3 as a molecular determinant of dynamic mechanosensitivity in mouse proprioceptors.