Adrenal chromaffin cells express two synaptotagmin isoforms, Syt-1 and Syt-7. Isoforms are usually sorted to separate secretory granules, are differentially activated by depolarizing stimuli, and favor discrete modes of exocytosis. It is proposed that stimulus/Ca+-dependent secretion in the chromaffin cell relies on selective Syt isoform activation.

Alzheimer’s disease (AD) therapies predominantly focus on β-amyloid (Aβ), but Aβ effects may be maximal before clinical symptoms appear. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. Rho-associated kinases (ROCK1 and ROCK2) regulate the actin cytoskeleton, and ROCK1 and ROCK2 protein abundances are increased in early AD. Here, we found that the increased abundance of ROCK1 in cultured primary rat hippocampal neurons reduced dendritic spine length through a myosin-based pathway, whereas the increased abundance of ROCK2 induced spine loss through the serine and threonine kinase LIMK1. Aβ42 oligomers can activate ROCKs. Here, using static imaging studies combined with multielectrode array analyses, we found that the ROCK2-LIMK1 pathway mediated Aβ42-induced spine degeneration and neuronal hyperexcitability. Live-cell microscopy revealed that pharmacologic inhibition of LIMK1 rendered dendritic spines resilient to Aβ42 oligomers. Treatment of hAPP mice with a LIMK1 inhibitor rescued Aβ-induced hippocampal spine loss and morphologic aberrations. Our data suggest that therapeutically targeting LIMK1 may provide dendritic spine resilience to Aβ and therefore may benefit cognitively normal patients that are at high risk for developing dementia.

Acid aspiration-induced lung injury is a common disease in the intensive care unit (ICU) and acute respiratory distress syndrome (ARDS). Hypoxia-inducible factor (HIF)-1α is a major transcription factor responsible for regulating the cellular response to changes in oxygen tension. A clear understanding of the function of HIF-1α in lung inflammatory response is currently lacking. Here, we sought to determine the role of HIF-1α in type 2 alveolar epithelial cells (AEC) in the generation of the acute inflammatory response following gastric aspiration (GA). GA led to profound hypoxia at very early time points following GA. This correlated to a robust increase in HIF-1α, tissue albumin and pro-inflammatory mediators following GA in AECs. The extent of lung injury and the release of pro/anti-inflammatory cytokines were significantly reduced in HIF-1α (−/−) mice. Finally, we report that HIF-1α upregulation of the acute inflammatory response is dependent on NF-κB following GA.

This study provides novel mechanistic insights into how Syt-1 and Syt-7 C2B domains regulate the later stages of exocytosis. We show that small structural differences within this region exert significant effects on fusion pore properties. We propose that these effects may arise from differences in C2B domain affinity for the plasma membrane.

Chromaffin cells release transmitters from populations of granules to which synaptotagmin-1 and synaptotagmin-7 are selectively sorted. Rao et al. characterize the functional properties of these granules and show that synaptotagmin-7 confers fast kinetics and high efficacy to the exocytotic event.