Descripción: Calcium signals are involved in a large variety of physiological processes. Their versatility relies on the diversity of spatiotemporal behaviors that the calcium concentration can display. Calcium entry through inositol 1,4,5-trisphosphate (IP3) receptors (IP3R's) is a key component that participates in both local signals such as "puffs" and in global waves. IP3R's are usually organized in clusters on the membrane of the endoplasmic reticulum and their spatial distribution has important effects on the resulting signal. Recent high resolution observations [1] of Ca2+ puffs offer a window to study intra-cluster organization. The experiments give the distribution of the number of IP3R's that open during each puff without much processing. Here we present a simple model with which we interpret the experimental distribution in terms of two stochastic processes: IP3 binding and unbinding and Ca2+-mediated inter-channel coupling. Depending on the parameters of the system, the distribution may be dominated by one or the other process. The transition between both extreme cases is similar to a percolation process. We show how, from an analysis of the experimental distribution, information can be obtained on the relative weight of the two processes. The largest distance over which Ca2+mediated coupling acts and the density of IP3-bound IP3R's of the cluster can also be estimated. The approach allows us to infer properties of the interactions among the channels of the cluster from statistical information on their emergent collective behavior. © 2010 Solovey, Dawson.

Descripción: Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects particularly motoneurons. Several pieces of evidence suggested the involvement of autoimmune mechanisms mediated by antibodies in ALS. However, the significance of those antibodies in the disease and the underlying mechanisms are unknown. Here we showed that IgG purified from a group of sporadic ALS patients, but not familial ALS patients, specifically interact with the presynaptic membrane of motoneurons through an antigen-antibody interaction and modulated synaptic transmission. Immunoreactivity against nerve terminals showed strong correlation with synaptic modulation ability. In addition, several controls have ruled out the possibility for this synaptic modulation to be mediated through proteases or nonspecific effects. Effective IgG potentiated both spontaneous and asynchronous transmitter release. Application of pharmacological inhibitors suggested that activation of this increased release required a nonconstitutive Ca2+ influx through N-type (Ca v2.2) channels and phospholipase C activity and that activation of IP3 and ryanodine receptors were necessary to both activate and sustain the increased release. Consistent with the notion that ALS is heterogeneous disorder, our results reveal that, in ∼50% of ALS patients, motor nerve terminals constitutes a target for autoimmune response. Copyright © 2006 Society for Neuroscience.