We review a multiscale model of saliva secretion describing in brief how the magic size is constructed and what we have so far learned from it. unimportance of acinar spatial structure for isotonic water transport (vi) the prediction that duct cells are highly depolarised (vii) the prediction the secondary saliva requires at least 1 mm (from your acinus) to reach ionic equilibrium. We end with a brief discussion of future directions for the model both in building and in the study of scientific questions. Go 6976 models and are arguably the most important challenge presently facing computational modellers in physiology. The challenge occurs not only because there are few available methods actually for the building let alone the analysis of such Go 6976 models. It also arises from the fact that every multiscale problem in physiology must be treated on its own merits possibly in a way quite different to every other exisiting multiscale model – a multiscale model of the heart for example may be of quite limited use in the building of multiscale models of the lung or the liver or the salivary gland – and thus in a sense different wheels need to be continuously reinvented. The multiscale model of saliva secretion that we present here is still a work in progress and we can still only request not solution many questions about the connection of spatial Spry4 structure and organ function. Nevertheless it has already contributed a significant amount to our understanding of how parotid acinar cells work and how they interact and is the first step along the path towards a greater understanding of salivary gland function from molecule to organ. 2 The physiology of saliva secretion Evaluations Go 6976 of the physiology of saliva secretion can be found in [9 10 11 12 1 13 14 15 Saliva is definitely secreted by three major pairs of glands – the sublingual submandibular and parotid glands – as well as from a large number of minor glands spread through the oral cavity. In each of the major glands main saliva is definitely produced by acinar cells which are grouped in grape-like clusters in the terminal branches of a tree-like branching system of ducts which are lined by duct cells. The primary saliva then travels along the ducts where its ionic composition is definitely revised by duct cells to produce secondary saliva which is definitely secreted into the oral cavity. Acinar cells are either serous or mucus with the proportion of each type determined by the gland and the varieties while duct cells also come in a variety of types each with different ion transport functions. Secondary saliva is typically about 99% water even though secretion from some glands can be a lot more viscous due to the presence of large amounts of mucus. The majority of saliva (humans typically produce about a litre each day) comes Go 6976 from the submandibular and parotid glands. Here we focus almost entirely within the parotid gland although data from additional glands is used if you will find no other options. 2.1 Acinar cells Parotid acinar cells are polarized epithelial cells Go 6976 (Fig. 1). The basolateral membrane faces to the extracellular space while the apical membrane faces into the lumenal compartment which is definitely where the main saliva is definitely secreted. Multiple acinar cells secrete into the same lumen a fact that may become important later when we consider the multicellular spatial structure. Number 1 The major ion channels involved in the secretion of saliva and their control by Ca2+. Although Ca2+-sensitve K+ channels are also situated within the apical membrane they may be omitted here for clarity. The basolateral membrane has a variety of ion exchangers and channels (Fig. 1) including the Na+/K+ ATPase a Na+/K+/Cl? cotransporter and a Ca2+-dependent K+ channel. Within the apical membrane the most important ion channel is definitely a Ca2+-dependent Cl? channel. Control of Ca2+ is vital (Fig. 2). Binding of an agonist to G-protein-coupled receptors (P2Y purinergic receptors for example or alpha-adrenergic receptors) results in the activation of phospholipase C (PLC) and thus production of inositol trisphosphate (IP3). This pathway is definitely important for the control of Ca2+ dynamics in almost all cell types and is described in much more fine detail in [16 17 18 19 20 21 IP3 binds to IP3 receptors (IPR) which are Ca2+ channels situated within the membrane of the endoplasmic reticulum (ER) resulting Go 6976 in the release of Ca2+ from your ER. Ca2+ can also be released from your ER through ryanodine receptors (RyR) or through a common small background leak (is an increasing function of Ca2+. Number 2 Summary of the important reactions involved in the control of Ca2+ in.