Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

Fan, Fan; Chen, Ji; Wu, Yumei; Ferguson, Shawn M.; Tamarina, Natalia A.; Philipson, Louis H.; Lou, Xuelin

doi:10.1172/jci80652

Cited by 39 publications

(66 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In β-cells, TrkA endocytosis may allow access to intracellular signaling effectors including actin modulatory proteins, prolong receptor activation, or allow localized responses at specific sub-cellular domains (Sorkin and von Zastrow, 2009). Interestingly, β-cell specific deletion of dynamin 2 resulted in a striking increase in F-actin density and impaired insulin secretion and glucose tolerance (Fan et al, 2015), similar to our observations with TrkA inactivation, raising the possibility that TrkA receptors may be a cargo for dynamin 2-mediated endocytosis in β-cells. Together, our findings suggest TrkA-harboring endosomes as a unique locus for regulatory control of insulin granule mobilization in β-cells.…”

Section: Discussionsupporting

confidence: 84%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

View full text Add to dashboard Cite

Summary Insulin secretion by pancreatic islet β-cells is critical for glucose homeostasis, and a blunted β-cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve Growth Factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β-cells. High glucose rapidly enhances NGF secretion, and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF, TrkA, or acute disruption of TrkA signaling impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins, and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β-cell dysfunction.

show abstract

Section: Discussionsupporting

confidence: 84%

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Dynamin can regulate actin function through direct and indirect interactions (65,82), and actin is important for bulk (68)(69)(70) and ultrafast endocytosis (72). Interestingly, dynamin KO leads to alteration of actin polymerization and reorganization in other types of cells (34,66). A role for actin in vesicle recruitment has also been reported (73,83,84).…”

Section: Discussionmentioning

confidence: 98%

“…Mouse brains (P18-20) were fixed and cut into 40-to 60-μm slices. Immunohistochemistry and confocal fluorescence imaging were performed as described previously (66). See SI Materials and Methods for details.…”

Section: Methodsmentioning

confidence: 99%

“…EPSCs were evoked by a bipolar electrode, and no offline R s correction was applied. Cm was measured using the Sine+DC technique under whole-cell patch clamp as described previously (28,66). Cm levels (%) after endocytosis recovery in fast and slow phases were calculated at 2 and 35 s, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…It is known that dynamin regulates actin function through direct and indirect interactions (65) and that the loss of dynamin strongly enhances actin reorganization (34,66). Therefore, actin may differentially contribute to endocytosis, as well as transmitter release, in cKO and control synapses.…”

Section: Actin Depolymerization Has a Stronger Effect On Synaptic Depmentioning

confidence: 99%

See 2 more Smart Citations

Tissue-specific dynamin-1 deletion at the calyx of Held decreases short-term depression through a mechanism distinct from vesicle resupply

Mahapatra

Fan

Lou

2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Dynamin is a large GTPase with a crucial role in synaptic vesicle regeneration. Acute dynamin inhibition impairs neurotransmitter release, in agreement with the protein's established role in vesicle resupply. Here, using tissue-specific dynamin-1 knockout [conditional knockout (cKO)] mice at a fast central synapse that releases neurotransmitter at high rates, we report that dynamin-1 deletion unexpectedly leads to enhanced steady-state neurotransmission and consequently less synaptic depression during brief periods of high-frequency stimulation. These changes are also accompanied by increased transmission failures. Interestingly, synaptic vesicle resupply and several other synaptic properties remain intact, including basal neurotransmission, presynaptic Ca 2+ influx, initial release probability, and postsynaptic receptor saturation and desensitization. However, acute application of Latrunculin B, a reagent known to induce actin depolymerization and impair bulk and ultrafast endocytosis, has a stronger effect on steady-state depression in cKO than in control and brings the depression down to a control level. The slow phase of presynaptic capacitance decay following strong stimulation is impaired in cKO; the rapid capacitance changes immediately after strong depolarization are also different between control and cKO and sensitive to Latrunculin B. These data raise the possibility that, in addition to its established function in regenerating synaptic vesicles, the endocytosis protein dynamin-1 may have an impact on short-term synaptic depression. This role comes into play primarily during brief highfrequency stimulation.short-term plasticity | release site clearance | dynamin | bulk endocytosis | actin S ustained neurotransmission requires synaptic vesicle (SV) recycling. The reformation of functional SVs, in general, requires several seconds or even longer (1, 2) and is thus several orders of magnitude slower than vesicle release at active zones (AZs). Vesicle fusion can reach rates of up to a few thousand vesicles per second in many types of nerve terminals, such as ribbon synapses (3,000/s) (3), cerebellar basket cell terminals (5,000/s) (4), and the calyx of Held (6,000/s) (5-7). Because release sites are limited in number, synapses need to reuse them rapidly in succession during repetitive stimulation, and this requirement may be more restrictive than that of SV availability (8). AZs are composed of a meshwork of evolutionarily conserved scaffold proteins including RIM, Munc-13, RIM-BP, α-liprin, ELKS, and Ca 2+ channels (9-11), but their dynamic properties are poorly understood (10). During high-frequency release, vesicle membrane components (12) and soluble N-Ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) proteins that occupy the release sites need to be cleared rapidly so that new vesicles can dock and prime for new rounds of exocytosis. The recovery of release sites may become rate-limiting during high rates of transmitter release (8). However, direct experimental testing is chall...

show abstract

Real-Time Endocytosis Measurements by Membrane Capacitance Recording at Central Nerve Terminals

Lou

2018

Clathrin-Mediated Endocytosis

View full text Add to dashboard Cite

Endocytosis is fundamental to cell function. It can be monitored by capacitance measurements under patch-clamp recordings. Membrane capacitance recording measures the cell membrane surface area and its changes at high temporal-resolution and sensitivity, and it is a powerful biophysical approach in the field of exocytosis and endocytosis. A popular one is the frequency domain method that entails processing passive sinusoidal membrane currents induced by a sinusoidal voltage. This technique requires a phase-sensitive detector or "lock-in amplifier" implemented in hardware or software during patch-clamp recordings. It has been widely used in many secretory cells, but its application directly at central presynaptic terminals is technically challenging. We have applied this technique to study synaptic endocytosis in the calyx of Held, a large glutamatergic synaptic terminal, as well as mouse pancreatic β-cells. The presynaptic capacitance measurements provide a unique alternative to measuring transmitter release and presynaptic endocytosis. Here, we describe this method at the calyx of Held in acute brain slices and provide a practical guide to obtaining high quality capacitance measurements at presynaptic terminals.

show abstract

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

Cited by 39 publications

References 96 publications

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion

Tissue-specific dynamin-1 deletion at the calyx of Held decreases short-term depression through a mechanism distinct from vesicle resupply

Real-Time Endocytosis Measurements by Membrane Capacitance Recording at Central Nerve Terminals

Contact Info

Product

Resources

About