I read with great interest the article entitled “Toward a concept of stretch coupling in smooth muscle: a thesis by Lars Thuneberg on contractile activity in neonatal interstitial cells of Cajal” written by Huizinga and colleagues that appeared in the September 2010 issue of your journal, and would like to congratulate Huizinga and colleagues on such a fine work in which they paid tribute to Lars Thuneberg by providing evidence for one of the important hypotheses he put forward (Huizinga et al., 2010). This article reminds the original ideas of Lars Thuneberg trying to demonstrate that “peg and socket junctions” might participate in a mechanical coupling and as stretch receptors located between interstitial cells of Cajal (ICC) and smooth muscle (Thuneberg and Peters, 2001). For this hypothesis to be valid, ICC should be able to rhythmically contract and communicate contractile information to smooth muscle cells and/or nerves.

As mentioned in the article, in the 1970s, Lars Thuneberg, together with Faussone Pellegrini, proposed the hypothesis that ICC are the pacemaker cells of the gut (Faussone Pellegrini et al., 1977; Thuneberg, 1982). For the first time, ICC were described by Santiago Ramón y Cajal, probably during his short stay in Barcelona (1887–1892) in collaboration with another Spanish histologist, La Villa. At that time, an important controversy existed because some researchers supported “the reticularist”, whereas others adhered to “the neuronist” theory. ICC (at that time ICC were considered neurons) were an important exception to the “neuronist” theory. In fact, ICC constitute a network of cells that orchestrate cyclic depolarizations and probably also participate in neurotransmission as Cajal suggested in his first descriptions (Garcia-Lopez et al., 2009).

Nowadays, cell communication is still an important debate. Calcium oscillations in ICC cause cyclic depolarizations that can spread to other ICC and smooth muscle cells through gap junctions (Torihashi et al., 2002; Park et al., 2006). There is no doubt that gap junctions are responsible for an electrical and metabolic coupling between cells. However, in some areas (especially in the longitudinal muscle), gap junctions are rare and it is difficult to demonstrate an electrical coupling. Consequently, the role of gap junctions in pacing is still controversial (Daniel et al., 2007). The present article is not an historical article at all. The authors have tried to translate the ideas of Lars Thuneberg (based on his notes) into a real and actual article that proposes a mechanical coupling that might contribute to the transmission of mechanical activity and such mechanical coupling probably also plays a role in stretch sensing.

It is well accepted that the network of ICC close to Auerbach's plexus is the main pacemaker area of the small intestine. However, in my work, under the supervision of Daniel, we proposed that the ICC network near the deep muscular plexus was an accessory pacemaker network (Jimenez et al., 1996). I remember a very interesting discussion in 2001 with Lars Thuneberg during his visit to Barcelona, when he was an external examiner for the thesis of Pluja et al. (2001). The idea that the ICC network of the deep muscular plexus is an accessory pacemaker system, which is consistent with the presence of high-density “peg and socket” junctions in this area. Lars Thuneberg hypothesized that peg and socket junctions can be stretch sensors that translate mechanical inputs to smooth muscle cells (Thuneberg and Peters, 2001). Peg and socket junctions can contribute to rhythmic (but not electrical) contractions found in the small intestine of newborn mice or Wv/Wv mice that lack a functional ICC-AP network.

The present article lends functional support to the idea that in some circumstances (in this case neonatal animals), ICC can contract and possibly transmit mechanical contractions through peg and socket junctions. This might be a mechanism that might participate in the regulation of gastrointestinal motility. It is impressive that the texts in quotation marks and italics stem from his notes, posters, figure legends, or e-mails. The text is absolutely faithful to the original idea of Lars Thuneberg. Some of the points of this article need further studies, for example, the molecular nature of the contractile activity or the fact that calcium imaging techniques that show a cyclic increase in calcium in ICC, are not related to cyclic contractile activity of ICC (Torihashi et al., 2002; Park et al., 2006). I am sure that this debate will be solved in the future by his friends and collaborators.


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  • Daniel EE, Yazbi AE, Mannarino M, Galante G, Boddy G, Livergant J, Oskouei TE. 2007. Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine? Am J Physiol Gastrointest Liver Physiol 292: G734G745.
  • Faussone Pellegrini MS, Cortesini C, Romagnoli P. 1977. Ultrastructure of the tunica muscularis of the cardial portion of the human esophagus and stomach, with special reference to the so-called Cajal's interstitial cells. Arch Ital Anat Embriol 82: 157177.
  • Garcia-Lopez P, Garcia-Marin V, Martinez-Murillo R, Freire M. 2009. Updating old ideas and recent advances regarding the interstitial cells of Cajal. Brain Res Rev 61: 154169.
  • Huizinga JD, Lammers WJ, Mikkelsen HB, Zhu Y, Wang XY. 2010. Toward a concept of stretch coupling in smooth muscle: a thesis by Lars Thuneberg on contractile activity in neonatal interstitial cells of Cajal. Anat Rec (Hoboken) 293: 15431552.
  • Jimenez M, Cayabyab FS, Vergara P, Daniel EE. 1996. Heterogeneity in electrical activity of the canine ileal circular muscle: interaction of two pacemakers. Neurogastroenterol Motil 8: 339349.
  • Park KJ, Hennig GW, Lee HT, Spencer NJ, Ward SM, Smith TK, Sanders KM. 2006. Spatial and temporal mapping of pacemaker activity in interstitial cells of Cajal in mouse ileum in situ. Am J Physiol Cell Physiol 290: C1411C1427.
  • Pluja L, Alberti E, Fernandez E, Mikkelsen HB, Thuneberg L, Jimenez M. 2001. Evidence supporting presence of two pacemakers in rat colon. Am J Physiol Gastrointest Liver Physiol 281: G255G266.
  • Thuneberg L. 1982. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol 71: 1130.
  • Thuneberg L, Peters S. 2001. Toward a concept of stretch-coupling in smooth muscle. I. Anatomy of intestinal segmentation and sleeve contractions. Anat Rec 262: 110124.
  • Torihashi S, Fujimoto T, Trost C, Nakayama S. 2002. Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae. J Biol Chem 277: 1919119197.

M. Jimenez* †, * Department of Cell Biology, Physiology and Immunology Universitat Autònoma de Barcelona (UAB) Bellaterra 08193, Spain, † Centro en Investigación Biomédica en Red de Enfermedades Hepáticas y Digest ivas (Ciberehd) Instituto de Salud Carlos III, Spain.