Vesicle Priming and Recruitment by ubMunc13-2 Are Differentially Regulated by Calcium and Calmodulin

Zikich, Dragloslav; Mezer, Aviv; Varoqueaux, Frédérique; Sheinin, Anton; Junge, Harald J.; Nachliel, Esther; Melamed, Rely; Brose, Nils; Gutman, Menachem; Ashery, Uri

doi:10.1523/jneurosci.5096-07.2008

Cited by 50 publications

(85 citation statements)

References 72 publications

(127 reference statements)

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“…Initially detected in human renal mesangial and cortical epithelial cells (Song et al, 1998), it is also present in mouse neuromuscular junctions (Varoqueaux et al, 2005) and brain (Betz et al, 2001;AndrewsZwilling et al, 2006;Breustedt et al, 2010), and at low levels in human neutrophils (Pivot-Pajot et al, 2008), bovine chromaffin cells (Zikich et al, 2008), and mouse airway goblet cells (Zhu et al, 2008). Using purified, isoform-specific antibodies (Figs.…”

Section: Discussionmentioning

confidence: 99%

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

Cooper

Hemmerlein²,

Ammermüller³

et al. 2012

Journal of Neuroscience

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Munc13 proteins are essential regulators of exocytosis. In hippocampal glutamatergic neurons, the genetic deletion of Munc13s results in the complete loss of primed synaptic vesicles (SVs) in direct contact with the presynaptic active zone membrane, and in a total block of neurotransmitter release. Similarly drastic consequences of Munc13 loss are detectable in hippocampal and striatal GABAergic neurons. We show here that, in the adult mouse retina, the two Munc13-2 splice variants bMunc13-2 and ubMunc13-2 are selectively localized to conventional and ribbon synapses, respectively, and that ubMunc13-2 is the only Munc13 isoform in mature photoreceptor ribbon synapses. Strikingly, the genetic deletion of ubMunc13-2 has little effect on synaptic signaling by photoreceptor ribbon synapses and does not prevent membrane attachment of synaptic vesicles at the photoreceptor ribbon synaptic site. Thus, photoreceptor ribbon synapses and conventional synapses differ fundamentally with regard to their dependence on SV priming proteins of the Munc13 family. Their function is only moderately affected by Munc13 loss, which leads to slight perturbations of signal integration in the retina.

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Section: Discussionmentioning

confidence: 99%

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

Cooper

Hemmerlein²,

Ammermüller³

et al. 2012

Journal of Neuroscience

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“…To establish the above hypothesis that Kv2.1 enhances vesicle recruitment, we stimulated exocytosis by flash photolysis of caged Ca 2+ , which causes step-like increases in [Ca 2+ ] i , enabling designation of the released vesicles to distinct pools (Becherer and Rettig, 2006;Zikich et al, 2008). Control cells displayed a typical biphasic increase in membrane capacitance, in which an exocytotic burst is followed by a sustained phase (component) of secretion (Fig.…”

Section: Kv21 Increases Vesicle Recruitment During Prolonged Stimulamentioning

confidence: 99%

Non-conducting function of the Kv2.1 channel enables it to recruit vesicles for release in neuroendocrine and nerve cells

Feinshreiber

Singer-Lahat

Friedrich

et al. 2010

Journal of Cell Science

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SummaryRegulation of exocytosis by voltage-gated K + channels has classically been viewed as inhibition mediated by K + fluxes. We recently identified a new role for Kv2.1 in facilitating vesicle release from neuroendocrine cells, which is independent of K + flux. Here, we show that Kv2.1-induced facilitation of release is not restricted to neuroendocrine cells, but also occurs in the somatic-vesicle release from dorsal-root-ganglion neurons and is mediated by direct association of Kv2.1 with syntaxin. We further show in adrenal chromaffin cells that facilitation induced by both wild-type and non-conducting mutant Kv2.1 channels in response to long stimulation persists during successive stimulation, and can be attributed to an increased number of exocytotic events and not to changes in single-spike kinetics. Moreover, rigorous analysis of the pools of released vesicles reveals that Kv2.1 enhances the rate of vesicle recruitment during stimulation with high Ca 2+ , without affecting the size of the readily releasable vesicle pool. These findings place a voltage-gated K + channel among the syntaxin-binding proteins that directly regulate pre-fusion steps in exocytosis.

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“…CaM regulates vesicle priming, recruitment, and short-term plasticity by interactions with Munc13 (Junge et al, 2004;Zikich et al, 2008;Rodríguez-Castañeda et al, 2010;Lipstein et al, 2012), which is responsible for Ca 2+ /CaM-dependent replenishment at the calyx of Held (Lipstein et al, 2013). However, deletion of Munc13 in photoreceptors had no effect on vesicle tethering to the ribbon and only modest effects on synaptic transmission measured with ERG recordings (Cooper et al, 2012), pointing toward a limited involvement of Munc13 in vesicle replenishment in photoreceptors.…”

Section: Potential Molecular Mechanisms Of Ca 2+ /Cam Effectsmentioning

confidence: 99%

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

Hook¹,

Parmelee²,

Chen³

et al. 2014

J Cell Biol

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At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca 2+ ) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant,  = 1/(Ds), where D is the vesicle diffusion coefficient,  is the vesicle diameter,  is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higherfrequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons.

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Vesicle Priming and Recruitment by ubMunc13-2 Are Differentially Regulated by Calcium and Calmodulin

Cited by 50 publications

References 72 publications

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

Non-conducting function of the Kv2.1 channel enables it to recruit vesicles for release in neuroendocrine and nerve cells

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

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