Skip to main content

Advertisement

SpringerLink
Log in

Mechanotransduction in epidermal Merkel cells

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The cellular and molecular basis of vertebrate touch reception remains least understood among the traditional five senses. Somatosensory afferents that innervate the skin encode distinct tactile qualities, such as flutter, slip, and pressure. Gentle touch is thought to be transduced by somatosensory afferents whose tactile end organs selectively filter mechanical stimuli. These tactile end organs comprise afferent terminals in association with non-neuronal cell types such as Merkel cells, keratinocytes, and Schwann cells. An open question is whether these non-neuronal cells serve primarily as passive mechanical filters or whether they actively participate in mechanosensory transduction. This question has been most extensively studied in Merkel cells, which are epidermal cells that complex with sensory afferents in regions of high tactile acuity such as fingertips, whisker follicles, and touch domes. Merkel cell-neurite complexes mediate slowly adapting type I (SAI) responses, which encode sustained pressure and represent object features with high fidelity. How Merkel cells contribute to unique SAI firing patterns has been debated for decades; however, three recent studies in rodent models provide some direct answers. First, whole-cell recordings demonstrate that Merkel cells are touch-sensitive cells with fast, mechanically activated currents that require Piezo2. Second, optogenetics and intact recordings show that Merkel cells mediate sustained SAI firing. Finally, loss-of-function studies in transgenic mouse models reveal that SAI afferents are also touch sensitive. Together, these studies identify molecular mechanisms of mechanotransduction in Merkel cells, reveal unexpected functions for these cells in touch, and support a revised, two-receptor site model of mechanosensory transduction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bechstedt S, Howard J (2008) Hearing mechanics: a fly in your ear. Curr Biol : CB 18(18):R869–R870. doi:10.1016/j.cub.2008.07.069

    Article  CAS  PubMed  Google Scholar 

  2. Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong D, Matzuk M, Bellen HJ, Zoghbi HY (2000) Functional conservation of atonal and Math1 in the CNS and PNS. Development 127(5):1039–1048

    CAS  PubMed  Google Scholar 

  3. Boulais N, Pennec JP, Lebonvallet N, Pereira U, Rougier N, Dorange G, Chesne C, Misery L (2009) Rat Merkel cells are mechanoreceptors and osmoreceptors. PLoS ONE 4(11):e7759. doi:10.1371/journal.pone.0007759

    Article  PubMed Central  PubMed  Google Scholar 

  4. Boulais N, Pereira U, Lebonvallet N, Gobin E, Dorange G, Rougier N, Chesne C, Misery L (2009) Merkel cells as putative regulatory cells in skin disorders: an in vitro study. PLoS ONE 4(8):e6528. doi:10.1371/journal.pone.0006528

    Article  PubMed Central  PubMed  Google Scholar 

  5. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K (2005) Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 8(9):1263–1268. doi:10.1038/nn1525

    Article  CAS  PubMed  Google Scholar 

  6. Cha M, Ling J, Xu GY, Gu JG (2011) Shear mechanical force induces an increase of intracellular Ca2+ in cultured Merkel cells prepared from rat vibrissal hair follicles. J Neurophysiol 106(1):460–469. doi:10.1152/jn.00274.2011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Chalfie M (2009) Neurosensory mechanotransduction. Nat Rev Mol Cell Biol 10(1):44–52. doi:10.1038/nrm2595

    Article  CAS  PubMed  Google Scholar 

  8. Chan E, Yung WH, Baumann KI (1996) Cytoplasmic Ca2+ concentrations in intact Merkel cells of an isolated, functioning rat sinus hair preparation. Exp Brain Res 108(3):357–366

    Article  CAS  PubMed  Google Scholar 

  9. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, Patapoutian A (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330(6000):55–60. doi:10.1126/science.1193270

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, Patapoutian A (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483(7388):176–181. doi:10.1038/nature10812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Delmas P, Hao J, Rodat-Despoix L (2011) Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nat Rev Neurosci 12(3):139–153. doi:10.1038/nrn2993

    Article  CAS  PubMed  Google Scholar 

  12. Diamond J, Mills LR, Mearow KM (1988) Evidence that the Merkel cell is not the transducer in the mechanosensory Merkel cell-neurite complex. Prog Brain Res 74:51–56

    Article  CAS  PubMed  Google Scholar 

  13. Fagan BM, Cahusac PM (2001) Evidence for glutamate receptor mediated transmission at mechanoreceptors in the skin. Neuroreport 12(2):341–347

    Article  CAS  PubMed  Google Scholar 

  14. Gottschaldt KM, Vahle-Hinz C (1981) Merkel cell receptors: structure and transducer function. Science 214(4517):183–186

    Article  CAS  PubMed  Google Scholar 

  15. Haeberle H, Bryan LA, Vadakkan TJ, Dickinson ME, Lumpkin EA (2008) Swelling-activated Ca2+ channels trigger Ca2+ signals in Merkel cells. PLoS ONE 3(3):e1750. doi:10.1371/journal.pone.0001750

    Article  PubMed Central  PubMed  Google Scholar 

  16. Haeberle H, Fujiwara M, Chuang J, Medina MM, Panditrao MV, Bechstedt S, Howard J, Lumpkin EA (2004) Molecular profiling reveals synaptic release machinery in Merkel cells. Proc Natl Acad Sci U S A 101(40):14503–14508. doi:10.1073/pnas.0406308101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Haeberle H, Lumpkin EA (2008) Merkel cells in somatosensation. Chemosens Percept 1(2):110–118. doi:10.1007/s12078-008-9012-6

    Article  PubMed Central  PubMed  Google Scholar 

  18. Halata Z, Grim M, Bauman KI (2003) Friedrich Sigmund Merkel and his “Merkel cell”, morphology, development, and physiology: review and new results. Anat Rec A: Discov Mol Cell Evol Biol 271(1):225–239. doi:10.1002/ar.a.10029

    Article  Google Scholar 

  19. Han X, Chow BY, Zhou H, Klapoetke NC, Chuong A, Rajimehr R, Yang A, Baratta MV, Winkle J, Desimone R, Boyden ES (2011) A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex. Front Syst Neurosci 5:18. doi:10.3389/fnsys.2011.00018

    Article  PubMed Central  PubMed  Google Scholar 

  20. Hao J, Delmas P (2010) Multiple desensitization mechanisms of mechanotransducer channels shape firing of mechanosensory neurons. J Neurosci : Off J Soc Neurosci 30(40):13384–13395. doi:10.1523/JNEUROSCI.2926-10.2010

    Article  CAS  Google Scholar 

  21. Hitchcock IS, Genever PG, Cahusac PM (2004) Essential components for a glutamatergic synapse between Merkel cell and nerve terminal in rats. Neurosci Lett 362(3):196–199. doi:10.1016/j.neulet.2004.02.071

    Article  CAS  PubMed  Google Scholar 

  22. Hu J, Lewin GR (2006) Mechanosensitive currents in the neurites of cultured mouse sensory neurones. J Physiol 577(Pt 3):815–828. doi:10.1113/jphysiol.2006.117648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Iggo A, Findlater G. Sensory receptor mechanisms. edited by W. Hamann 8:. A. Iggo© 1984 World Scientific Publ. Co., Singapore. In: Proceedings of the International Symposium on Sensory Receptor Mechanisms, 1984. p 117

  24. Iggo A, Muir AR (1969) The structure and function of a slowly adapting touch corpuscle in hairy skin. J Physiol 200(3):763–796

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Ikeda I, Yamashita Y, Ono T, Ogawa H (1994) Selective phototoxic destruction of rat Merkel cells abolishes responses of slowly adapting type I mechanoreceptor units. J Physiol 479(Pt 2):247–256

    Article  PubMed Central  PubMed  Google Scholar 

  26. Ikeda R, Cha M, Ling J, Jia Z, Coyle D, Gu JG (2014) Merkel cells transduce and encode tactile stimuli to drive abeta-afferent impulses. Cell 157(3):664–675. doi:10.1016/j.cell.2014.02.026

    Article  CAS  PubMed  Google Scholar 

  27. Johnson KO (2001) The roles and functions of cutaneous mechanoreceptors. Curr Opin Neurobiol 11(4):455–461. doi:10.1016/S0959-4388(00)00234-8

    Article  CAS  PubMed  Google Scholar 

  28. Johnson KO, Lamb GD (1981) Neural mechanisms of spatial tactile discrimination: neural patterns evoked by braille-like dot patterns in the monkey. J Physiol 310:117–144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Kinkelin I, Stucky CL, Koltzenburg M (1999) Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75. Eur J Neurosci 11(11):3963–3969

    Article  CAS  PubMed  Google Scholar 

  30. Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci : Off J Soc Neurosci 29(15):4808–4819. doi:10.1523/JNEUROSCI.5380-08.2009

    Article  CAS  Google Scholar 

  31. Lesniak DR, Marshall KL, Wellnitz SA, Jenkins BA, Baba Y, Rasband MN, Gerling GJ, Lumpkin EA (2014) Computation identifies structural features that govern neuronal firing properties in slowly adapting touch receptors. eLife 3:e01488. doi:10.7554/eLife.01488

    Article  PubMed Central  PubMed  Google Scholar 

  32. Lumpkin EA, Collisson T, Parab P, Omer-Abdalla A, Haeberle H, Chen P, Doetzlhofer A, White P, Groves A, Segil N, Johnson JE (2003) Math1-driven GFP expression in the developing nervous system of transgenic mice. Gene Expr Pattern : GEP 3(4):389–395

    Article  CAS  PubMed  Google Scholar 

  33. Lumpkin EA, Hudspeth AJ (1995) Detection of Ca2+ entry through mechanosensitive channels localizes the site of mechanoelectrical transduction in hair cells. Proc Natl Acad Sci U S A 92(22):10297–10301

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Ma Q (2014) Merkel cells are a touchy subject. Cell 157(3):531–533. doi:10.1016/j.cell.2014.04.010

    Article  CAS  PubMed  Google Scholar 

  35. Maksimovic S, Baba Y, Lumpkin EA (2013) Neurotransmitters and synaptic components in the Merkel cell-neurite complex, a gentle-touch receptor. Ann N Y Acad Sci 1279:13–21. doi:10.1111/nyas.12057

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz SA, Firozi P, Woo SH, Ranade S, Patapoutian A, Lumpkin EA (2014) Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509:617–621. doi:10.1038/nature13250

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Maricich SM, Morrison KM, Mathes EL, Brewer BM (2012) Rodents rely on Merkel cells for texture discrimination tasks. J Neurosci : Off JSoc Neurosci 32(10):3296–3300. doi:10.1523/JNEUROSCI.5307-11.2012

    Article  CAS  Google Scholar 

  38. Maricich SM, Wellnitz SA, Nelson AM, Lesniak DR, Gerling GJ, Lumpkin EA, Zoghbi HY (2009) Merkel cells are essential for light-touch responses. Science 324(5934):1580–1582. doi:10.1126/science.1172890

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Merkel F (1875) Tastzellen und Tastkörperchen bei den Hausthieren und beim Menschen. Arch Mikrosk Anat 11(1):636–652. doi:10.1007/BF02933819

    Article  Google Scholar 

  40. Mills LR, Diamond J (1995) Merkel cells are not the mechanosensory transducers in the touch dome of the rat. J Neurocytol 24(2):117–134

    Article  CAS  PubMed  Google Scholar 

  41. Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM (2009) Mammalian Merkel cells are descended from the epidermal lineage. Dev Biol 336(1):76–83. doi:10.1016/j.ydbio.2009.09.032

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Nilius B, Biro T, Owsianik G (2014) TRPV3: time to decipher a poorly understood family member! J Physiol 592(Pt 2):295–304. doi:10.1113/jphysiol.2013.255968

    Article  CAS  PubMed  Google Scholar 

  43. Nunzi MG, Pisarek A, Mugnaini E (2004) Merkel cells, corpuscular nerve endings and free nerve endings in the mouse palatine mucosa express three subtypes of vesicular glutamate transporters. J Neurocytol 33(3):359–376. doi:10.1023/B:NEUR.0000044196.45602.92

    Article  CAS  PubMed  Google Scholar 

  44. Nurse C, Cooper E (1988) Electrophysiological studies on Merkel cells isolated from rat vibrissal mechanoreceptors. In: Hník P, Soukup T, Vejsada R, Zelená J (eds) Mechanoreceptors. Springer, New York, pp 189–194. doi:10.1007/978-1-4899-0812-4_35

    Chapter  Google Scholar 

  45. Pacitti EG, Findlater GS (1988) Calcium channel blockers and Merkel cells. Prog Brain Res 74:37–42

    Article  CAS  PubMed  Google Scholar 

  46. Pawson L, Prestia LT, Mahoney GK, Guclu B, Cox PJ, Pack AK (2009) GABAergic/glutamatergic-glial/neuronal interaction contributes to rapid adaptation in pacinian corpuscles. J Neurosci : Off J Soc Neurosci 29(9):2695–2705. doi:10.1523/JNEUROSCI.5974-08.2009

    Article  CAS  Google Scholar 

  47. Phillips JR, Johnson KO (1985) Neural mechanisms of scanned and stationary touch. J Acoust Soc Am 77(1):220–224

    Article  CAS  PubMed  Google Scholar 

  48. Piskorowski R, Haeberle H, Panditrao MV, Lumpkin EA (2008) Voltage-activated ion channels and Ca2+-induced Ca2+ release shape Ca2+ signaling in Merkel cells. Pflugers Archiv: Eur J Physiol 457(1):197–209. doi:10.1007/s00424-008-0496-3

    Article  CAS  Google Scholar 

  49. Poole K, Herget R, Lapatsina L, Ngo HD, Lewin GR (2014) Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch. Nat Commun 5:3520. doi:10.1038/ncomms4520

    Article  PubMed Central  PubMed  Google Scholar 

  50. Press D, Mutlu S, Guclu B (2010) Evidence of fast serotonin transmission in frog slowly adapting type 1 responses. SomatosensMot Res 27(4):174–185. doi:10.3109/08990220.2010.516670

    Article  Google Scholar 

  51. Reinisch CM, Tschachler E (2005) The touch dome in human skin is supplied by different types of nerve fibers. Ann Neurol 58(1):88–95. doi:10.1002/ana.20527

    Article  PubMed  Google Scholar 

  52. Rugiero F, Drew LJ, Wood JN (2010) Kinetic properties of mechanically activated currents in spinal sensory neurons. J Physiol 588(Pt 2):301–314. doi:10.1113/jphysiol.2009.182360

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Senok SS, Baumann KI, Halata Z (1996) Selective phototoxic destruction of quinacrine-loaded Merkel cells is neither selective nor complete. Exp Brain Res 110(3):325–334

    Article  CAS  PubMed  Google Scholar 

  54. Soya M, Sato M, Sobhan U, Tsumura M, Ichinohe T, Tazaki M, Shibukawa Y (2014) Plasma membrane stretch activates transient receptor potential vanilloid and ankyrin channels in Merkel cells from hamster buccal mucosa. Cell Calcium 55(4):208–218. doi:10.1016/j.ceca.2014.02.015

    Article  CAS  PubMed  Google Scholar 

  55. Tachibana T, Endoh M, Fujiwara N, Nawa T (2005) Receptors and transporter for serotonin in Merkel cell-nerve endings in the rat sinus hair follicle. An Immunohistochemical Study. Arch Histol Cytol 68(1):19–28

    Article  CAS  PubMed  Google Scholar 

  56. Tachibana T, Nawa T (2002) Recent progress in studies on Merkel cell biology. Anat Sci Int 77(1):26–33. doi:10.1046/j.0022-7722.2002.00008.x

    Article  PubMed  Google Scholar 

  57. Tazaki M, Suzuki T (1998) Calcium inflow of hamster Merkel cells in response to hyposmotic stimulation indicate a stretch activated ion channel. Neurosci Lett 243(1–3):69–72

    Article  CAS  PubMed  Google Scholar 

  58. van den Pol AN (2012) Neuropeptide transmission in brain circuits. Neuron 76(1):98–115. doi:10.1016/j.neuron.2012.09.014

    Article  PubMed Central  PubMed  Google Scholar 

  59. Van Keymeulen A, Mascre G, Youseff KK, Harel I, Michaux C, De Geest N, Szpalski C, Achouri Y, Bloch W, Hassan BA, Blanpain C (2009) Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 187(1):91–100. doi:10.1083/jcb.200907080

    Article  PubMed Central  PubMed  Google Scholar 

  60. Wellnitz SA, Lesniak DR, Gerling GJ, Lumpkin EA (2010) The regularity of sustained firing reveals two populations of slowly adapting touch receptors in mouse hairy skin. J Neurophysiol 103(6):3378–3388. doi:10.1152/jn.00810.2009

    Article  PubMed Central  PubMed  Google Scholar 

  61. Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z, Petrus M, Miyamoto T, Reddy K, Lumpkin EA, Stucky CL, Patapoutian A (2014) Piezo2 is required for Merkel-cell mechanotransduction. Nature 509:622–626. doi:10.1038/nature13251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Woodbury CJ, Koerber HR (2007) Central and peripheral anatomy of slowly adapting type I low-threshold mechanoreceptors innervating trunk skin of neonatal mice. J Comp Neurol 505(5):547–561. doi:10.1002/cne.21517

    Article  PubMed  Google Scholar 

  63. Yamashita Y, Akaike N, Wakamori M, Ikeda I, Ogawa H (1992) Voltage-dependent currents in isolated single Merkel cells of rats. J Physiol 450:143–162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Yamashita Y, Ogawa H (1991) Slowly adapting cutaneous mechanoreceptor afferent units associated with Merkel cells in frogs and effects of direct currents. Somatosens Mot Res 8(1):87–95

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Ms. Blair Jenkins for assistance with figures and members of the Lumpkin lab for discussions. The authors are supported by National Institutes of Health grants R01AR051219 (to EAL) and R01NS073119 (to EAL and Gregory J. Gerling), and fellowships to MN (Japan Society for the Promotion of Science Research Fellowships for Young Scientists 24-7585) and SM (F32NS080544).

Author information

Authors and Affiliations

  1. Department of Dermatology, Columbia University, 1150 St. Nicholas Avenue, room 302B, New York, NY, 10032, USA

    Masashi Nakatani, Srdjan Maksimovic, Yoshichika Baba & Ellen A. Lumpkin

  2. Graduate School of System Design and Management, Keio University, Yokohama, Japan

    Masashi Nakatani

  3. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA

    Ellen A. Lumpkin

  4. Program in Neurobiology and Behavior, Columbia University, New York, NY, USA

    Ellen A. Lumpkin

Authors
  1. Masashi Nakatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Srdjan Maksimovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshichika Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ellen A. Lumpkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ellen A. Lumpkin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakatani, M., Maksimovic, S., Baba, Y. et al. Mechanotransduction in epidermal Merkel cells. Pflugers Arch - Eur J Physiol 467, 101–108 (2015). https://doi.org/10.1007/s00424-014-1569-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1569-0

Keywords

Search

Navigation