Molecular determinants of mechanosensation in the muscle spindle

Abstract

The muscle spindle (MS) provides essential sensory information for motor control and proprioception. The Group Ia and II MS afferents are low threshold slowly-adapting mechanoreceptors and report both static muscle length and dynamic muscle movement information. The exact molecular mechanism by which MS afferents transduce muscle movement into action potentials is incompletely understood. This short review will discuss recent evidence suggesting that PIEZO2 is an essential mechanically sensitive ion channel in MS afferents and that vesicle-released glutamate contributes to maintaining afferent excitability during the static phase of stretch. Other mechanically gated ion channels, voltage-gated sodium channels, other ion channels, regulatory proteins, and interactions with the intrafusal fibers are also important for MS afferent mechanosensation. Future studies are needed to fully understand mechanosensation in the MS and whether different complements of molecular mediators contribute to the different response properties of Group Ia and II afferents.

Figure 1. Similarity in mechanosensation in the muscle spindle and Merkel cell-neurite complex.

Xanthurenic acid (XA) was used to block the packaging of glutamate into synaptic-like vesicles and MS afferent response to ramp-and-hold stretch and sinusoidal vibration assayed before and after XA. MS afferent firing was decreased or eliminated during ramp-and-hold stretch in the majority of afferents tested and firing at the end of stretch was affected earliest (a). Even in some units that could not maintain firing during stretch, the response to vibration was unchanged (b; same unit as a; [34•]), suggesting vesicle-released glutamate is required for static but not dynamic response to stretch likely via effects on general afferent excitability, (c) Similarly, in the Merkel cell-associated Aβ afferent, preventing the Merkel cell from releasing synaptic vesicles (K14^Cre;R26^TeNT) preferentially decreased firing during the hold phase of touch as compared to littermate controls (R26^TeNT). A similar reduction in static touch response occurs if Merkel cells are eliminated [37], PIEZO2 in Merkel cells is eliminated [9,10], or the β2 receptor is eliminated from the Aβ afferent [39], (d). The mechanosensation model proposed for the Merkel cell–neurite complex [39] is similar to that proposed here for the MS afferent. Touch is thought to open PIEZO2 channels in the Aβ afferent to mediate the initial response. Opening of PIEZO2 in the Merkel cell then leads to synaptic-like vesicle release which is necessary for the static phase response via some unknown pathway. Panels a and b taken from [34•] and c and d from Ref. [39].

Figure 2. Molecular contributors to mechanosensation in muscle spindle afferents.

(a) Schematic of the muscle spindle (MS), which is innervated by Group Ia and II MS afferents as well gamma motor neuron efferents. (b) Sensory endings in the MS afferent (gray) require the mechanically sensitive non-specific cation channel PIEZO2 for normal function [7]. TMEM150c/Tentonin-3 is found in MS afferent endings and has been shown to enhance PIEZO2 current and increase the time to inactivation [25,26•]. Additional mechanically sensitive ion channels have been found in MS afferents, including DEG/ENaC and TRP family members, but future work is needed to understand their role in mechanosensation [2••,27,31]. Synaptic-like vesicles containing glutamate are released in a stretch and calcium-dependent manner and are necessary for maintaining afferent excitability and static sensitivity [32,34•]. The glutamate receptor(s) (GluR) and signaling pathway(s) necessary to mediate the glutamate-induced effects are currently unknown. Voltage-gated sodium channels (Nav) are located on MS afferent sensory endings and presumably amplify receptor current as it travels to the spike generating heminode [43••]. Additional ion channels are necessary for receptor current generation and different complements of ion channels may underlie differences in sensitivity of MS afferent subtypes [3••]. Mechanical interactions with the intrafusal fiber bag and chain fibers are also important for MS afferent mechanosensation. Acetylcholine is released from the MS afferent ending and binds to acetylcholine receptors on intrafusal fibers and decreases afferent sensitivity [47••]. (c) The heminode is the site of action potential generation and the complement of Nav and potassium channels and other ion channels can shape the slowly adapting response of the MS afferent to stretch ([5,43••]; raw trace of MS afferent response to stretch in mouse shown above). Abbreviations: VGLUT1 (vesicular glutamate transporter 1), VAChT (vesicular acetylcholine transporter), GluR (glutamate receptor), AChR (acetylcholine receptor). Figure modified from [34•]. Created with BioRender.com.