Interstitial cells of Cajal (ICC) is a peculiar cell network composed of cells having processes described by the eminent Spanish neuroanatomist of the 19th century, S. Ramon y Cajal. ICC became a fascinating subject to many investigators and it is estimated that there are over 100 publications yearly on the subject related to ICC, in the last three years. Now it is widely accepted that ICC are pace maker cells of the gut and probable progenitor cells of gastrointestinal stromal tumors (GIST). Lately, interstitial Cajal-like cells (ICLC) are being found in various organs and their physiological role is still to be defined. We have reviewed the literature trying to evaluate the validity of the current concept and found that there are a few salient points to be considered. 1) There has been some important departure in defining the identity of ICC from the original criteria of Cajal. In particular, ICC with myoid feafures in intestinal smooth muscle layers (ICC-DPM) do not seem to fit to the original description of interstitial cell network by Cajal. We have also pointed out that the current reports assigning a pace maker role to ICC vastly depend on the scientific data on "ICC with myoid features", not on "fibroblast-like ICC", which are more abundant and easier to identify. 2) There seem to be an overwhelming amount of data proving the relationship between ICC and GIST. Both are known to express c-Kit and the ultrastructural characteristics seen in GIST roughly parallel those of ICC including minimal myoid differentiation seen in the majority of GIST, supporting the current concept that GIST are ICC tumors. 3) According to the original description of Cajal, ICC was not limited to the gut, suggesting an existence of ICC in other organs. The list of organs reported to contain ICC (currently identified by immunohistochemistry and electron microscopy) is ever growing and further studies are needed to define their identity and pathophysiologic role. 4). Recent data concerning gut development suggest that both c-Kit expressing ICC (fibroblasts-like as well as muscle-like) and gut muscle cells derive from the common progenitor cells of the embryonic gut unifying the histogenetic concept of all GIST with heterogeneous cytomorphologic features. In this review we attempted to incorporate recent information on interstitial Cajal-like cells (ICLC) found in other organs to broaden our understanding of ICC in general in terms of their ultrastructure, physiology, and neoplasia.

Membrane fusion is a sine qua non process for cell physiology. It is critical for membrane biogenesis, intracellular traffic, and cell secretion. Although investigated for over a century, only in the last 15 years, the molecular machinery and mechanism of membrane fusion has been deciphered. The membrane fusion event elicits essentially three actors on stage: anionic phospholipids ‐ phosphatidylinositols, phosphatidyl serines, specific membrane proteins, and the calcium ions, all participating in a well orchestrated symphony. Three soluble N‐ethylmaleimide‐sensitive factor (NSF)‐attachment protein receptors (SNAREs) have been implicated in membrane fusion. Target membrane proteins, SNAP‐25 and syntaxin (t‐SNARE) and secretory vesicle‐associated membrane protein (v‐SNARE) or VAMP were discovered in the 1990's and suggested to be the minimal fusion machinery. Subsequently, the molecular mechanism of SNARE‐induced membrane fusion was discovered. It was demonstrated that when t‐SNARE‐associated lipid membrane is exposed to v‐SNARE‐associated vesicles in the presence of Ca²⁺, the SNARE proteins interact in a circular array to form conducting channels, thus establishing continuity between the opposing bilayers. Further it was proved that SNAREs bring opposing bilayers close to within a distance of 2‐3 Å, allowing Ca²⁺ to bridge them. The bridging of bilayers by Ca²⁺ then leads to the expulsion of water between the bilayers at the contact site, allowing lipid mixing and membrane fusion. Calcium bridging of opposing bilayers leads to the release of water, both from the water shell of hydrated Ca²⁺ ions, as well as the displacement of loosely coordinated water at the phosphate head groups in the lipid membrane. These discoveries provided for the first time, the molecular mechanism of SNARE‐induced membrane fusion in cells. Some of the seminal discoveries are briefly discussed in this minireview.