Mechanosensitive Channels: Multiplicity of Families and Gating Paradigms
Total Page：16
File Type：pdf, Size：1020Kb
R EVIEW Mechanosensitive Channels: Multiplicity of Families and Gating Paradigms Sergei Sukharev1* and David P. Corey2* (Published 10 February 2004) Mechanosensitive ion channels are the primary and comprise just a few GTP-binding protein (G protein)–cou- transducers that convert mechanical force into an pled receptor second-messenger pathways (1–3). Given these electrical or chemical signal in hearing, touch, and examples, should we be looking for universal mechanotransduc- other mechanical senses. Unlike vision, olfaction, tion mechanisms within these various systems and presume that and some types of taste, which all use similar kinds the primary receiver elements are essentially the same, but are of primary heterotrimeric GTP-binding protein–cou- tuned differently depending on the setting? If not, are there dif- pled receptors, mechanosensation relies on diverse ferent types of mechanoreceptors that use similar biophysical types of transducer molecules. Unrelated types of principles but dissimilar molecular mechanisms, which arose channels can be used for the perception of various independently many times in the course of evolution? The ex- mechanical stimuli, not only in distant groups of or- amples discussed below suggest that the latter scenario is more ganisms, but also in separate locations of the same likely. Although incomplete, the available molecular data sug- organism. The extreme sensitivity of the transduction gest a multiplicity of structural designs and mechanisms of mechanism in the auditory system, which relies on mechanoreceptors not only across the tree of life, but also with- an elaborate structure of rigid cilia, filamentous in single organisms. This diversity implies that careful analysis links, and molecular motors to focus force on trans- of individual systems will be required before generalizations duction channels, contrasts with that of the bacterial can be made. channel MscL, which is opened by high lateral ten- sion in the membrane and fulfills a safety-valve The Nature of the Primary Transducer rather than a sensory function. The spatial scales of Hearing, vestibular function, and touch—senses that involve conformational movement and force in these two specialized organs, such as the ear and the cutaneous tactile re- systems are described, and are shown to be consis- ceptors, and are present in both vertebrates and invertebrates— tent with a general physical description of mechani- represent the fastest and most sensitive mechanosensory sys- cal channel gating. We outline the characteristics of tems known. In addition to these specialized organs, free so- several types of mechanosensitive channels and the matosensory endings and visceral afferents are diffusely spread functional contexts in which they participate in sig- through many tissues; many possess substantial mechanosensi- naling and cellular regulation in sensory and non- tivity, which allows them to monitor cutaneous stretch and de- sensory cells. formation, limb position, vascular and alveolar distension, and the filling of the stomach or bladder. All of these functions are Introduction attributed to the presence of mechanosensitive ion channels Mechanosensation is ubiquitous and takes on many different (MS channels) embedded in the plasma membranes of sensory forms, as cells, tissues, and entire organisms constantly receive cells (4, 5). In contrast to second messenger–mediated transduc- and generate various mechanical stimuli. Sounds captured by tion in other senses, the ion channels in mechanosensors are be- the ear and static loads on bone represent two extreme examples lieved to be directly activated by mechanical forces, for the fol- of stimuli with vastly different magnitudes and time courses. Yet lowing reasons: (i) An electrical current through the sensory organisms can gauge these stimuli separately by using different cell membrane (receptor current), a consequence of ion channel receptors and integration schemes. Inputs to the central nervous opening, appears to be the earliest recorded event following the system (CNS) from specialized mechanosensory organs initiate mechanical stimulus and it precedes other sequelae of the stim- an array of homeostatic reflexes and behaviors. At the same ulus. (ii) Many mechanosensory responses occur on a submil- time, various physiological responses to force can be observed lisecond time scale, which is faster than that permitted by a sec- at the level of single cells, demonstrating that mechanoreceptors ond-messenger cascade (6). The receptor current in the sensory are indeed ubiquitous. cell or nerve ending causes a receptor potential, which—in all Because mechanosensory phenomena are so diverse, the but the smallest animals—is converted into action potentials in progress of unraveling the underlying molecular mechanisms afferent nerve fibers passing to the CNS. In addition to special has been slower than with studies of other senses. Indeed, in the sensory organs and nerve endings, MS channels are found in mechanisms of olfaction, vision, and some types of taste, the various somatic nonsensory cells, where they are presumed to sets of molecular players appear to be evolutionarily conserved modulate the processes of contraction and secretion in response to mechanical stress, or to regulate cell volume or turgor. 1Department of Biology, University of Maryland, College Park, MD Although they open rapidly and are easy to assay, MS chan- 20742, USA. 2Howard Hughes Medical Institute and Department of nels are not the only primary receptors for mechanical stimuli. Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Neurotransmitter release dependent on mechanical stress (7), *Corresponding authors. E-mail: [email protected] (S.S), slow responses to static load such as cell and tissue remodeling [email protected] (D.P.C.) (8), and gene expression and proliferative reactions (9) may in- www.stke.org/cgi/content/full/sigtrans;2004/219/re4 Page 1 R EVIEW volve integrins and associated signaling pathways. It has been mechanistic paradigms of their gating: channels to which force proposed that in certain organs, stress-induced adenosine is conveyed by distinct cytoskeletal proteins (often in special- triphosphate (ATP) release may exert a paracrine action on ized sensory cells), and channels gated by tension in the lipid purinergic receptors in sensory fibers (10). Further studies will (best characterized in prokaryotes). clarify whether this purinergic stimulus causes afferent excita- tion directly or just modulates it. These related but mechanisti- Channel Gating by External Force cally separate processes will not be discussed here. Instead, we At its simplest, a MS channel is a specialized molecule—usual- focus on MS channels, which constitute a heterogeneous group ly a protein—in the cell membrane that can undergo a distortion of membrane proteins in their own right that are unified mostly in response to an external force, which either opens or closes a by function. conductive pathway through the molecule. The force can be ap- There are several systems for classifying MS channels, as plied either through cytoskeletal and extracellular matrix ele- outlined below. Conventionally, families of cloned channels are ments attached to the channel, or through the lipid bilayer itself assigned according to sequence homology. Grouping channels (11). Such a distortion can be described as a conformational according to the tissue of origin (for instance, sensory versus transition between inactive (closed) and active (open) states nonsensory) is historical and reflects two complementary ap- separated by a barrier (12, 13). In the simple case of a two-state proaches: genetic and electrophysiological. Genetic studies be- channel opened by linear force (Fig. 1A), the open probability gin with screens for mutations that affect sensory function and po is described by a Boltzmann relation: lead to identification of the chromosomal loci, genes, and even- tually proteins (not necessarily channels) responsible for the function of a specific sensory organ. The MS channels from the DEG/ENaC and TRP families were identified genetically. Elec- trophysiological surveys, in contrast, first identify conductance as a functional manifestation of the channel. This approach led (Eq. 1) to the identification of MS channel activity in neurons and also in numerous nonneural cells. Using electrophysiology, channel where f is the force acting on the channel, b is the distance it activities can be further characterized with pharmacological and moves when it opens (the swing of the gate), ∆u is an intrinsic biochemical tools that may suggest the type of molecule re- energy difference between open and closed states that biases the sponsible for the function. For example, the bacterial MS chan- probability distribution toward the closed state in the absence of −21 nel MscL was identified through a biochemical approach, using applied force, and kBT is thermal energy (~4 × 10 J at room patch-clamp as an assay technique. Genetic and electrophysio- temperature). The equation predicts a sigmoidal dependence of logical approaches complement each other and are often used in po on applied force with the midpoint (po = 0.5) at f = ∆u/b. To combination. The two-pore domain MS channels, for instance, open the channel, the product of f and b must be several times were cloned by homology to potassium channels and were iden- thermal energy; for instance, it requires a change of 6 kBT to go tified as mechanosensitive only upon