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

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.

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