Ca2+ signalling underlying pancreatitis.

In spite of significant scientific progress in recent years, acute pancreatitis (AP) is still a dangerous and in up to 5% of cases deadly disease with no specific cure. It is self-resolved in the majority of cases, but could result in chronic pancreatitis (CP) and increased risk of pancreatic cancer (PC). One of the early events in AP is premature activation of digestive pro-enzymes, including trypsinogen, inside pancreatic acinar cells (PACs) due to an excessive rise in the cytosolic Ca2+ concentration, which is the result of Ca2+ release from internal stores followed by Ca2+ entry through the store operated Ca2+ channels in the plasma membrane. The leading causes of AP are high alcohol intake and biliary disease with gallstones obstruction leading to bile reflux into the pancreatic duct. Recently attention in this area of research turned to another cause of AP - Asparaginase based drugs - which have been used quite successfully in treatments of childhood acute lymphoblastic leukaemia (ALL). Unfortunately, Asparaginase is implicated in triggering AP in 5-10% of cases as a side effect of the anti-cancer therapy. The main features of Asparaginase-elicited AP (AAP) were found to be remarkably similar to AP induced by alcohol metabolites and bile acids. Several potential therapeutic avenues in counteracting AAP have been suggested and could also be useful for dealing with AP induced by other causes. Another interesting development in this field includes recent research related to pancreatic stellate cells (PSCs) that are much less studied in their natural environment but nevertheless critically involved in AP, CP and PC. This review will attempt to evaluate developments, approaches and potential therapies for AP and discuss links to other relevant diseases.

Estimating transmitter release rates and quantal amplitudes in central synapses from postsynaptic current fluctuations.

Several approaches recently introduced to analyze release rates in central synapses advanced our understanding of synaptic neurotransmission, however, leaving many questions still unresolved. In this work we present evidence that a new method recently developed by Sakaba and Neher to study neurotransmission in calyx of Held, a giant glutamatergic synapse, could be also applied for estimating release rate functions and averaged quantal sizes in small central synapses. By means of different simulation approaches applied to reproduce GABAergic neurotransmission in the hippocampus we have shown that possible problems with a spatial voltage clamp which can occur in synaptic connections distributed over a large area of dendritic tree are not crucial for applicability of the method when synapses are compactly distributed or located proximally and when release rates are below 1 ms(-1). In another set of simulations we have also shown that at above mentioned release rates desensitization and/or saturation of postsynaptic GABAA receptors does not prevent accurate estimates of release rate and averaged quantal size. Thus, we conclude that the new approach based on analysis of fluctuations of postsynaptic currents under conditions of stationary release or moderately nonstationary conditions might be applicable to studies of small central synapses.