Our research focuses on understanding the molecular mechanisms underlying neurotransmitter secretion with the goal of providing novel insight into how neuronal function is regulated in the nervous system.
Mechanisms of neuropeptide secretion in ultradian rhythms:
Neuropeptides play important roles in regulating many physiological processes and behaviors, such as aging, metabolism and locomotion, and defects in the release of neuropeptides contribute to disease, such as diabetes and neurological disorders. Neuropeptides are packaged into dense core vesicles (DCVs). DCVs differ from synaptic vesicles (SVs) in that they are secreted at different subcellular locations, are larger than SVs and carry different contents. These differences suggest that exocytosis of DCVs and SVs are differentially regulated and that DCV secretion will be regulated by unique molecules, many of which are unknown. We have identified a new function of the Parkinson’s protein, LRRK2, in promoting the maturation of dense core vesicles that store and release a neuropeptide from a neuron that is rhythmically activated. We found that LRRK2 functions with specific intracellular membrane trafficking proteins to control the protein composition of dense core vesicles in axons. This work may reveal the pathogenic mechanism for LRRK mutations in Parkinson’s patients which is not understood.
Circuitry controlling a rhythmic behavior:
We have
identified a function for a cell in C. elegans called hmc, which is not a neuron, muscle, skin, or gut cell, in controlling the execution of an ultradian rhythmic behavior. Through genetic analysis and live calcium imaging we found that this cell controls a specific muscle contraction important for the digestion of bacteria and that it is rhythmically activated every 50 seconds when animals are actively eating. We identified a neuroendocrine signal and a G protein coupled receptor that activate the cell, and we found that activation leads to muscle contraction through gap junction-mediated coupling to muscle. We think this cell is most similar to the endothelial cells lining the blood vessels, and this system may be a good model to study the mechanisms of activation of endothelial cells by neuroendocrine signals.
Regulation of neuropeptide secretion by oxidative stress:
Stress response pathways play a critical role in mediating adaptive responses to cellular stress, and defend against neurodegeneration, aging and cancer. We found that reactive oxygen species (ROS) generated in the mitochondria in axons of specific interneurons promote neuropeptide secretion, and that the local generation of hydrogen peroxide by mitochondria promotes the exocytosis of a specific neuropeptide from dense core vesicle where it is stored at release sites. Release of this neuropeptide promotes organism-wide protection from oxidative stress by activating the conserved SKN-1/Nfr2 oxidative stress pathway. These findings show that the stress-regulated secretion of neuropeptides elicits a coordinated, systemic response to promote survival of the organism in response to oxidative stress, and this may represent a conserved mechanism by which neurons signal upon metabolic stress.
The role of sphingolipid signaling in mitochondrial surveillance:
Sphingolipids are bioactive lipids with diverse functions in cellular development and function. We discovered a novel role for a cascade of sphingolipid metabolism enzymes at mitochondria in promoting the activation of the mitochondrial unfolded protein response. We found that the lipid sphingosine-1-phosphate (S1P) at mitochondria is critical for this process, and that the enzymatic generation of S1P by sphingosine kinase is tightly regulated by mitochondrial stress. This work defines a novel role for local sphingolipid metabolism at mitochondria in stress responses, and establishes a potentially new mechanism by which mitochondrial stress triggers stress responses in humans.
How do electrical synapses synchronize synaptic output:
Electrical synapses and chemical synapses play important roles in synaptic transmission, but evidence supporting their interaction in vivo has not been well described. Using a combination of genetics, behavioral analysis and live calcium imaging, we have found that electrical synapses formed by the gap junction protein INX-1/innexin couples the presynaptic terminals of two neurons, AVL and DVB, to synchronize their activation and to promote GABA release in response to a pacemaker signal. We propose that electrical synapses function to ensure the robust execution of a rhythmic behavior both by coordinating the activities of presynaptic terminals in response pacemaker signaling, and by suppressing their activation when pacemaker signaling is low.
tags: Derek Sieburth lab elegans USC