Work

Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe

Year: 2016

Type: article

Abstract: Professor Goyal discounts a role for interstitial cells in neuromuscular transmission in gastrointestinal (GI) muscles (Goyal, 2016), but current knowledge supersedes his arguments because interstitial cells of Cajal (ICC) and PDGFRα+ cells: (1) are anatomically in close association with sites of neurotransmitter release (Wang et al. 1999), (2) are innervated by motor neurons (Iino et al. 2004; Baker et al. 2015), (3) express receptors for enteric neurotransmitters (Chen et al. 2007), (4) display transduction pathways and coupling between receptors and ion channels affecting the conductance of the smooth muscle cells (SMCs)–ICC–PDGFRα+ cells (SIP) syncytium (Iino et al. 2009; Zhu et al. 2011; Lies et al. 2014), and (5) are electrically coupled to SMCs, allowing conduction of electrical signals generated in one type of SIP cell to all others (Sanders et al. 2014). The net conductance of the SIP syncytium is relevant to excitation–contraction coupling because a voltage-dependent rise in Ca2+ in SMCs initiates contraction. The anatomy and physiology of the GI muscles favour the view that enteric motor responses are the integrated responses of SIP cells. Professor Goyal's use of 'mandatory' and 'obligatory' constricts his thinking to the obsolete notion that physiological responses might be exclusive to one component of the SIP syncytium. His views appear constrained by observations that mechanical responses to NO and ACh persist when most ICC fail to develop; thus interstitial cells are not 'obligatory participants' in neuromuscular responses. The question should be whether responses are normal when a cellular component of the SIP syncytium is reduced, because this may be the question of greatest clinical relevance. For example, new pathways for Ca2+ sensitization were unleashed by reduction of ICC in the gastric fundus (Bhetwal et al. 2013). The consequence of this might be to render responses to all other agonists abnormal. Could this contribute to the changes in proximal stomach compliance associated with symptoms experienced in gastric dyspepsia and gastroparesis? If so, a goal for treatments might be regeneration of ICC or at least restoration of physiological Ca2+ sensitivity. Reduction in guanylyl cyclase in oesophageal ICC reduced swallow-induced (i.e. neurally induced) relaxation (Groneberg et al. 2014). Thus, restoring nitrergic transduction in ICC might enhance lower oesophageal sphincter function in achalasia. Limiting hypotheses to enteric neurons and their interactions with SMCs has failed to produce efficacious therapies for most GI motility disorders. Anointing one cell or another as 'mandatory' or 'obligatory' for neuromuscular responses neglects the integrative and emergent properties of the SIP syncytium and hinders comprehension of the multicellular nature of neuromuscular responses. Understanding the responses of the SIP syncytium will provide a more holistic concept of enteric motor responses and might serve as a paradigm for developing 21st century therapeutics. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a 'Last Word'. Please email your comment, including a title and a declaration of interest, to [email protected]. Comments will be moderated and accepted comments will be published online only as 'supporting information' to the original debate articles once discussion has closed. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Source: The Journal of Physiology

DOI: 10.1113/jp271971

Authors: Kenton M. Sanders, Sean M. Ward, Andreas Friebe

Institutions: University of Nevada, Reno, University of Würzburg

Language: English

Topic: Gastrointestinal motility and disorders

Subfield: Gastroenterology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institute of Diabetes and Digestive and Kidney Diseases