Elsevier

Autonomic Neuroscience

Volume 153, Issues 1–2, 16 February 2010, Pages 58-68
Autonomic Neuroscience

Molecular basis of mechanosensitivity

https://doi.org/10.1016/j.autneu.2009.07.017Get rights and content

Abstract

An organism's ability to perceive mechanical stimuli is vital in determining how it responds to environmental challenges. External mechanosensation is responsible for the senses of touch, hearing, proprioception and aspects of somatic pain. Internally, mechanosensation underlies the initiation of autonomic reflex control and all manner of visceral sensations including chronic pain. Despite our increased knowledge of the molecular identity of invertebrate proteins that convert mechanical stimuli into electrical signals, understanding the complete molecular basis of mammalian mechanotransduction is currently a major challenge. Although the number of candidate molecules that serve as mechanotransducers is ever increasing, debate currently rages as to whether or not they contribute directly or indirectly to mammalian mechanotransduction. Despite these controversies novel molecules have been identified and their contribution to mechanosensation, be it direct or indirect, have improved our understanding of the mechanisms underlying visceral mechanosensation. Moreover, they have provided potential new pharmacological strategies for the control of visceral pain.

Introduction

Mechanotransduction is the conversion of mechanical forces into electrical signals. The speed required for this conversion suggests ion channels are gated in direct response to mechanical force. Therefore to be considered a molecular component of mechanotransduction a given protein must be located within the mechanoreceptor, particularly at the site where mechanical stimuli is detected (Gillespie and Walker, 2001). Genetic and localization studies in Caenorhabditis elegans (C-elegans) and Drosophila have provided much of the groundwork for determining the families of ion channels implicated in all other forms of mechanotransduction (Fig. 1). These studies suggest the Degenerin/Epithelial Na+ Channels (DEG/ENaC) and Transient Receptor Potential (TRP) families of ion channels form molecular components of the mechanotransduction complex which detects mechanical stimuli. These channels have been located within a wide variety of mechanoreceptors in a multitude of species and disruption of these channels results in alterations in the detection of the mechanical environment (Gillespie and Walker, 2001, Welsh et al., 2002, Goodman et al., 2004, Lumpkin and Bautista, 2005, Corey, 2006, Lumpkin and Caterina, 2007). However, a currently overlooked area for review is the field of visceral mechanotransduction. As such, this review will focus on recent published work on the molecular mechanisms with which visceral neurons transduce mechanical signals. In particular this review will focus on the mechanisms underlying intestinal mechanosensation as bladder sensation will be discussed elsewhere in this issue. Other models and systems of mechanosensation will be discussed initially for a historical perspective to understand the current leading candidates in mechanotransduction. However, it is becoming clear that visceral afferents might detect mechanical stimuli using different mechanisms than somatic afferents, inner ear hair cells or neurons in lower species (Fig. 1, Fig. 3).

Section snippets

Mechanisms underlying the transduction of mechanical stimuli

The key components in the process of mechanotransduction are speed and sensitivity. First, mechanotransduction needs to be fast and therefore mechanical forces need be focused directly to transduction channels (Gillespie and Walker, 2001). Secondly, mechanotransduction requires exquisite sensitivity so that varying grades of mechanical forces can be immediately directed to a mechanotransduction complex in the membrane. This rapidly opens the channel and amplifies the signal by allowing entry of

Controversies: direct or indirect channel activation?

In principle these mechanisms appear relatively straight forward. However, in many instances it is difficult to demonstrate how a particular channel contributes to mechanosensation. The channel may be directly activated by mechanical force, as above, or alternatively it may act indirectly as part of a downstream signalling pathway from the mechanotransduction complex (Fig. 2B). Contrasting data from different systems has lead to controversies surrounding the mechanosensitive nature of various

Functional classes of afferent in the murine gastrointestinal tract

Vagal gastro-oesophageal afferents can be classed into 2 subtypes, mucosal or tension (Page et al., 2002). Mucosal afferents respond to very fine mucosal stroking whilst tension sensitive afferents respond to stretch or distension (Page et al., 2002, Bielefeldt and Davis, 2008). These tension sensitive afferents are also known as, distension sensitive afferents, wide-dynamic range afferents or intraganglionic laminar endings (IGLES) in other species (Blackshaw et al., 2007). In the jejunum 3

Is visceral mechanosensation quick enough for direct mechanical gating?

The speed of visceral mechanosensation in the upper and lower gut suggests that activation via mechanogated ion channels located on afferent endings is responsible for visceral mechanotransduction. In guinea-pig the mechanotransduction delay for low intensity stretch sensitive (muscular like) afferents was shown to be < 2 ms in the rectum and 6 ms for vagal oesophageal mechanoreceptors. Mechanosensory responses are unaltered in 0 mM Ca2+, which prevents rapid exocytotic transmitter release (

Acid Sensing Ion Channel 1 (ASIC1)

Interest in ASIC1 as a mechanosensory molecule stemmed from its close relationship to invertebrate DEG/ENaC channels and observations by the Welsh and Lewin laboratories of alterations in somatic mechanosensory function in ASIC2 and ASIC3 −/− mice (discussed below). However, loss of ASIC1 has no significant effect on any of the 5 populations of cutaneous mechanoreceptor (Page et al., 2004). In the viscera the Blackshaw laboratory demonstrated, with fluorescence in situ hybridisation in

P2X purinoceptors

ATP is released from damaged cells and as such has a major role in signalling nociceptive events. P2X agonists evoke direct excitation of intestinal afferents. However, this can induce varying effects on intestinal mechanosensitivity ranging from either no change, to increased or decreased mechanosensitivity (Kirkup et al., 1999, Wynn et al., 2003, Wynn et al., 2004, Zagorodnyuk et al., 2003, Zagorodnyuk et al., 2005, Brierley et al., 2005a, Rong et al., 2009). Of all the candidates discussed

Concluding remarks

It is becoming clear from the literature that a variety of mechanisms underlie mechanosensation. It is apparent that visceral afferents may detect mechanical stimuli using fundamentally different mechanisms than those required in other systems. There are clear similarities in the molecular mechanisms underlying mechanosensation between different regions of gut (ASIC3, TRPV1 and TRPA1). However, there is also clear disparity between different regions of gut and between different afferent

Acknowledgements

I thank the National Health and Medical Research Council of Australia for an NHMRC Australian Biomedical Fellowship and project grant support at the Royal Adelaide Hospital and The University of Adelaide (LAB, SMB, GYR). I am especially grateful to Prof L. Ashley Blackshaw and Dr Grigori Y. Rychkov for ongoing discussions concerning the mechanistic idiosyncrasies and nuances of mechanotransduction. I thank Prof Michael J. Welsh, Dr Margaret P. Price, Dr John A. Wemmie (University of Iowa, USA),

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