The ric-3 gene is required for maturation of nicotinic acetylcholine receptors in Caenorhabditis elegans. The human homolog of RIC-3, hRIC-3, enhances expression of ␣7 nicotinic receptors in Xenopus laevis oocytes, whereas it totally abolishes expression of ␣4␤2 nicotinic and 5-HT 3 serotonergic receptors. Both the N-terminal region of hRIC-3, which contains two transmembrane segments, and the C-terminal region are needed for these differential effects. hRIC-3 inhibits receptor expression by hindering export of mature receptors to the cell membrane. By using chimeric proteins made of ␣7 and 5-HT 3 receptors, we have shown that the presence of an extracellular isoleucine close to the first transmembrane receptor fragment is responsible for the transport arrest induced by hRIC-3. Enhancement of ␣7 receptor expression occurs, at least, at two levels: by increasing the number of mature receptors and facilitating its transport to the membrane. Certain amino acids of a putative amphipathic helix present at the large cytoplasmic region of the ␣7 subunit are required for these actions. Therefore, hRIC-3 can act as a specific regulator of receptor expression at different levels.

SummarySynaptic vesicles loaded with neurotransmitters fuse with the plasma membrane to release their content into the extracellular space, thereby allowing neuronal communication. The membrane fusion process is mediated by a conserved set of SNARE proteins: vesicular synaptobrevin and plasma membrane syntaxin and SNAP-25. Recent data suggest that the fusion process may be subject to regulation by local lipid metabolism. Here, we have performed a screen of lipid compounds to identify positive regulators of vesicular synaptobrevin. We show that sphingosine, a releasable backbone of sphingolipids, activates synaptobrevin in synaptic vesicles to form the SNARE complex implicated in membrane fusion. Consistent with the role of synaptobrevin in vesicle fusion, sphingosine upregulated exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and hippocampal neurons, but not in neurons obtained from synaptobrevin-2 knockout mice. Further mechanistic insights suggest that sphingosine acts on the synaptobrevin/phospholipid interface, defining a novel function for this important lipid regulator.

Objective To estimate the prevalence and incidence of dementia and cognitive impairment without dementia (CIND) in the Mexican population. Methods The MHAS study is a prospective panel study of health and aging in Mexico with 7,000 elders that represent 8 million subjects nationally. Using measurements of cognition and activities of daily living of dementia cases and CIND were identified at baseline and follow up. Overall incidence rates and specific rates for sex, age and education were calculated. Results Prevalence was 6.1% and 28.7% for dementia and CIND, respectively. Incidence rates were 27.3 per 1,000 person-years for dementia and 223 per 1,000 persons-year for CIND. Rates of dementia and CIND increased with advancing age and decreased with higher educational level; sex had a differential effect depending on the age strata. Hypertension, diabetes and depression were risk factors for dementia but not for CIND. Discussion These data provide estimates of prevalence and incidence of dementia and cognitive impairment in the Mexican population for projection of future burden.

Chromaffin cell exocytosis is a fascinating interplay between secretory vesicles and cellular components. One of these components is the cytoskeleton and its associated regulatory proteins. Transport of chromaffin secretory granules from their site of biosynthesis towards the active site of exocytosis requires both F-actin fine remodelling as well as microtubule trails. At least two molecular motors, myosins II and V, seem to play a crucial role in the control of F-actin dynamics and vectorial vesicle displacement respectively. Vesicle movement experiences spatial restrictions as they approach the cell cortical region, where the F-actin meshwork constitutes a barrier-limiting vesicle access to the plasmalemma. During secretion, cortical F-actin is locally disrupted providing access of vesicles to release sites on the plasmalemma. Removal of the stimulus restores cortical F-actin. Two pathways (Ca2+-scinderin and PKC-MARCKS) control F-actin changes during the secretory cycle . Furthermore, GTPases such as RhoA, that controls F-actin network integrity, and Cdc42 signalling which induces the formation of local actin filaments at active sites, provide additional evidence on the importance of F-actin as a key element in vesicle transport and in the exocytotic machinery of chromaffin cells.