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Hypertension. 2004;44:616-617
Published online before print September 20, 2004, doi: 10.1161/01.HYP.0000144467.43205.ed
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(Hypertension. 2004;44:616.)
© 2004 American Heart Association, Inc.

Editorial Commentaries

Sensing Tension

Recognizing ENaC as a Stretch Sensor

Dale J. Benos

From the University of Alabama, Birmingham.

Correspondence to Dale J. Benos, Department of Physiology and Biophysics, University of Alabama-Birmingham, 1918 University Blvd, 706 BHSB, Birmingham, AL 35294-0005, E-mail benos{at}physiology.uab.edu

Homeostasis demands the integration and processing of a myriad of different input signals from a variety of sources. Regulation of central blood pressure is one such homeostatic system that depends critically on both volumetric and hemodynamic information. A common element for cardiovascular data transfer is sensing mechanical alterations such as cellular volume changes, changes in shear stresses, or changes in membrane tension or curvature. Stretch activation of membrane proteins, specifically ion channels, transduces hydrostatic pressure differences in the major blood vessels (via aortic and carotid baroreceptors) and small arteries and arterioles (via vascular smooth muscle cells [VSMCs]). Electrical signals from the baroreceptors travel via afferent nerves to integrative centers in the brain for processing, and appropriate efferent signals are generated to alter heart rate and peripheral resistance in a classic negative feedback loop. In contrast, there are important local autoregulatory control mechanisms that exist to alter blood flow in the capillary beds of the kidney, musculature, intestine, heart, and brain. These local effectors are also under central control to adjust peripheral vascular resistance when necessary. Presumptive mechanosensitive ion channels in VSMCs lining the arterioles are thought to subserve this function.

Until now, the identity of VSMC mechanosensitive channels was left to one’s musings. Wu and Davis1 reported a stretch-activated cation current in porcine coronary VSMCs. This current was blocked by hexamethylamiloride and Grammostolla spatulata venom, both of which are thought to block mechanosensitive channels.1–3 Golestaneh et al4 established that amiloride-sensitive, epithelial Na+ channels (ENaCs) were expressed in a vascular endothelial cell line. The article by Drummond, Gebremedhin, and Harder5 strongly implicates members of the ENaC superfamily as playing a major role in VSMC mechanotransduction. By an impressive array of molecular biological, immunologic, biochemical, and physiological techniques, they conclusively demonstrate that at least ß-ENaC and {gamma}-ENaC message and protein are present in rat VSMCs obtained from rat cerebral arterioles. Moreover, these investigators show that amiloride and benzamil, which are relatively high-affinity inhibitors of ENaC, effectively block the myogenic response (ie, stretch-induced vasoconstriction) of isolated and perfused rat brain arteries. However, Ditting et al6 concluded, on the basis of the inability of either amiloride or benzamil to block mechanically induced currents in rat cardiac ganglion nodosum cells, that ENaC is not an essential component of the cardiac mechanosensitive afferent reflex pathway.

Although individual ion channels have been shown to display characteristics consistent with being mechanosensitive, the channels responsible for mechanical transduction in most pressure-sensitive receptors (eg, inner ear hair cells, Pacinian corpuscles, baroreceptors) have not been, or are just starting to be, identified. For example, mechanical perturbations of membrane tension or shear have been shown to gate directly (ie, change the single-channel open probability) prokaryotic channels (MscL and MscS),7 Shaker potassium channels,8,9 N-type calcium channels,10 and ENaC.11–15 Before the report by Drummond et al,5 it was only in the arterial baroreceptor complex,16 inner ear hair cells,17,18 spider VS-3 slit-sense organ,19 dorsal root ganglion,20,21 osteoblasts,12 and in mammalian pain and touch receptors22 that any evidence concerning the molecular identification of components of ion channels that may subserve mechanosensation was proffered. Significantly, members of the degenerin (DEG)/ENaC superfamily surfaced in each of these systems.

The potential of ENaC and other family members to act as sensors of mechanical stress was first suggested in the initial cloning article of Canessa et al.23 Because of the high degree of amino acid homology between {alpha}-ENaC and the C. elegans proteins deg-1 and mec-4, proteins essential for touch sensitivity of the worm, Canessa et al (1993) believed that ENaC and the degenerins shared similar functions, especially controlling and sensing cellular volume. Yet, not everyone embraces the concept that DEG/ENaC are biological mechanosensors.24–27 Although definitive proof is not available, it is hard to ignore the fact that DEG/ENaC components routinely turn up in structures designed to sense mechanical perturbations.

So then, what is the mechanism of mechanotransduction? How does a change in mechanical stress gate ENaC or any other mechanosensitive ion channel? Hamill and Martinac28 summarized 3 possibilities: (1) bilayer tension or curvature directly activating a channel; (2) release of another molecule from a cell that in turn activates the channel; and (3) a tethering mechanism in which the ion channel binds either to the cytoskeleton or the extracellular matrix. Any movement of this network, say by a cell volume change or a direct mechanical force distorting the shape of the membrane, would "stress" the structure and hence gate the channel. Evidence exists to support all 3 mechanisms, especially for ENaC. Most investigators favor a tethered model,22,29,30 but mechanosensitive properties can also be attributed to ENaC, MscL, MscS, and even gramicidin when these channels are studied devoid of any apparent attachments.7,13,28,31,32 The reader is referred to an article by Morris and Homann33 for a wonderfully lucid discussion of lipid bilayer versus cytoskeleton contributions to membrane tension.

The work of Drummond et al5 does leave some important questions unanswered. One such question is: What is the composition of the functional mechanosensitive channel in VSMC? Although ß-ENaC and {gamma}-ENaC were identified, {alpha}-ENaC was not. {alpha}-ENaC is the core subunit of the channel because ß-ENaC and {gamma}-ENaC, alone or in combination, cannot form a functional unit.34 However, Drummond et al5 did not probe for other family members, such as acid-sensing ion channels or {delta}-ENaC; these can easily combine with ß-ENaC and {gamma}-ENaC to form functional channels.35 Regardless, if anyone doubts the power of mechanosensation on the cardiovascular system, consider this (inspired by Shakespeare’s Venus and Adonis, verses 95–96, 115, with sincere apologies)36:

"O, pity," gan she cry. "Flint-hearted boy!

’Tis but a kiss I beg, why art thou coy?

Touch but my lips with those fair lips of thine –

And my blood pressure shall rise, like leaves of a vine.

My skin shall flush with the color of love.

My heart shall pound, like the wings of a dove.

My head shall throb with pulsatile flow.

And serenity shall vanish, like an elusive doe."

Fortunately, this work by Drummond et al5 provides us with the beginnings of a mechanistic understanding of the first step of this youthful fancy.

Footnotes

The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association.

References

  1. Wu X, David MJ. Characterization of stretch-activated cation current in coronary smooth muscle cells. Am J Physiol Heart Circ Physiol. 2001; 280: H1751–H1761.[Abstract/Free Full Text]
  2. Chen Y, Simasko SM, Niggel J, Sigurdson WJ, Sachs F. Ca2+ uptake in GH3 cells during hypotonic swelling: the sensory role of stretch-activated ion channels. Am J Physiol Cell Physiol. 1996; 270: C1790–C1798.[Abstract/Free Full Text]
  3. Hu H, Sachs F. Mechanically activated currents in chick heart cells. J Membr Biol. 1996; 154: 205–216.[CrossRef][Medline] [Order article via Infotrieve]
  4. Golestaneh N, Klein C, Valamanesh F, Suarez G, Agarwal MK, Mirshahi M. Mineralocorticoid receptor-mediated signaling regulates the ion gated sodium channel in vascular endothelial cells and requires an intact cytoskeleton. Biochem Biophy Res Comm. 2001; 280: 1300–1306.[CrossRef][Medline] [Order article via Infotrieve]
  5. Drummond HA, Gebremedhin D, Harder DR. DEG/ENaC proteins: components of a vascular mechanosensor. Hypertension. 2004; 44: 643–648.[Abstract/Free Full Text]
  6. Ditting T, Linz P, Hilgers KF, Jung O, Geiger H, Veelken R. Putative role of epithelial sodium channels (ENaC) in the afferent limb of cardio renal reflexes in rats. Basic Res Cardiol. 2003; 98: 388–400.[CrossRef][Medline] [Order article via Infotrieve]
  7. Blount P. Molecular mechanisms of mechanosensation: big lessons from small cells. Neuron. 2003; 37: 731–734.[CrossRef][Medline] [Order article via Infotrieve]
  8. Gu CX, Juranka PF, Morris CE. Stretch-activation and stretch-inactivation of Shaker-IR, a voltage-gated K+ channel. Biophys J. 2001; 80: 2678–2693.[Abstract/Free Full Text]
  9. Laitko U, Morris CE. Membrane tension accelerates rate-limiting voltage-dependent activation and slow inactivation steps in a Shaker channel. J Gen Physiol. 2004; 123: 135–154.[Abstract/Free Full Text]
  10. Calabrese B, Tabarean IV, Juranka P, Morris CE. Mechanosensitivity of N-type calcium channel currents. Biophys J. 2002; 83: 2560–2574.[Abstract/Free Full Text]
  11. Achard JM, Bubien JK, Benos DJ, Warnock DG. Stretch modulates amiloride sensitivity and cation selectivity of sodium channels in human B lymphocytes. Am J Physiol Cell Physiol. 1996; 270: C224–C234.[Abstract/Free Full Text]
  12. Kizer N, Guo X-L, Hruska K. Reconstitution of stretch-activated cation channels by expression of the {alpha}-subunit of the epithelial sodium channel cloned from osteoblasts. Proc Nat Acad Sci U S A. 1997; 94: 1013–1018.[Abstract/Free Full Text]
  13. Ismailov II, Berdiev BK, Shlyonsky VG, Benos DJ. Mechanosensitivity of an epithelial Na+ channel in planar lipid bilayers: release from Ca2+ block. Biophys J. 1997; 72: 1182–1192.[Abstract/Free Full Text]
  14. Satlin LM, Sheng S, Woda CB, Kleyman TR. Epithelial Na+ channels are regulated by flow. Am J Physiol Renal Physiol. 2001; 280: F1010–F1018.[Abstract/Free Full Text]
  15. Ma HP, Li L, Zhou ZH, Eaton DC, Warnock DG. ATP masks stretch activation of epithelial sodium channels in A6 distal nephron cells. Am J Physiol Renal Physiol. 2002; 282: F501–F505.[Abstract/Free Full Text]
  16. Drummond HA, Price MP, Welsh MJ, Abboud FM. A molecular component of the arterial baroreceptor mechanotransducer. Neuron. 1998; 21: 1435–1441.[CrossRef][Medline] [Order article via Infotrieve]
  17. Furness DN, Hackney CM, Benos DJ. The binding site on cochlear stereocilia for antisera raised against renal Na+ channels is blocked by amiloride and dihydrostreptomycin. Hear Res. 1996; 93: 136–146.[CrossRef][Medline] [Order article via Infotrieve]
  18. Hudspeth AJ, Choe Y, Mehta AD, Martin P. Putting ion channels to work: mechanoelectrical transduction, adaptation, and amplification by hair cells. Proc Natl Acad Sci U S A. 2000; 97: 11765–11772.[Abstract/Free Full Text]
  19. Höger U, French AS. Extracellular acid increases the open probability of transduction channels in spider mechanoreceptors. Eur J Neurosci. 2002; 16: 2311–2316.[Medline] [Order article via Infotrieve]
  20. McCarter GC, Reichling DB, Levine JD. Mechanical transduction by rat dorsal root ganglion neurons in vitro. Neurosci Lett. 1999; 273: 179–182.[CrossRef][Medline] [Order article via Infotrieve]
  21. Garcia-Anoveros J, Samad TA, Zuvela-Jelaska L, Woolf CJ, Corey DP. Transport and localization of the DEG/ENaC ion channel BnaC1 alpha to peripheral mechanosensory terminals of dorsal root ganglia neurons. J Neurosci. 2001; 21: 2678–2686.[Abstract/Free Full Text]
  22. Welsh MJ, Price MP, Xie J. Biochemical basis of touch perception: mechanosensory function of degenerin/epithelial Na+ channels. J Biol Chem. 2002; 277: 2369–2372.[Free Full Text]
  23. Canessa CM, Horisberger J-D, Rossier BC. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature. 1993; 361: 467–470.[CrossRef][Medline] [Order article via Infotrieve]
  24. Awayda MS, Subramanyam M. Regulation of the epithelial Na+ channel by membrane tension. J Gen Physiol. 1998; 112: 97–111.[Abstract/Free Full Text]
  25. Rossier B. Mechanosensitivity of the epithelial sodium channel (ENaC): controversy or pseudocontroversy? J Gen Physiol. 1998; 112: 95–96.[Free Full Text]
  26. Rusch A, Hummler E. Mechano-electrical transduction in mice lacking the alpha-subunit of the epithelial sodium channel. Hear Res. 1999; 131: 170–176.[CrossRef][Medline] [Order article via Infotrieve]
  27. Roza C, Puel J-L, Kress M, Baron A, Diochot S, Lazdunski M, Waldmann R. Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. J Physiol. 2004; 558.2: 659–669.
  28. Hamill OP, Martinac B. Molecular basis of mechanotransduction in living cells. Physiol Rev. 2001; 81: 685–740.[Abstract/Free Full Text]
  29. Markin VS, Hudspeth AJ. Gating-spring models of mechanoelectrical transduction by hair cells of the internal ear. Annu Rev Biophys Biomol Struct. 1995; 24: 59–83.[CrossRef][Medline] [Order article via Infotrieve]
  30. Garcia-Aòoveros J, Corey DP. The molecules of mechanosensation. Annu Rev Neurosci. 1997; 20: 567–594.[CrossRef][Medline] [Order article via Infotrieve]
  31. Sukharev S, Anishkin A. Mechanosensitive channels: what can we learn from "simple" model systems? Trends Neurosci. 2004; 27: 345–350.[CrossRef][Medline] [Order article via Infotrieve]
  32. Suchyna TM, Tape SE, Koeppe II RE, Andersen OS, Sachs F, Gottlieb PA. Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature. 2004; 430: 235–240.[CrossRef][Medline] [Order article via Infotrieve]
  33. Morris CE, Homann U. Cell surface area regulation and membrane tension. J Membr Biol. 2001; 179: 79–102.[Medline] [Order article via Infotrieve]
  34. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger J-D, Rossier BC. Amiloride-sensitivie epithelial Na+ channel is made of three homologous subunits. Nature. 1994; 367: 463–467.[CrossRef][Medline] [Order article via Infotrieve]
  35. Ji H-L, Benos DJ. Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel. J Biol Chem. 2004; 279: 26939–26947.[Abstract/Free Full Text]
  36. The Complete Works of William Shakespeare. http://jollyroger.com/shakespeare/venus.html.




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