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The Journal of Neuroscience, January 31, 2007, 27(5):1200-1210; doi:10.1523/JNEUROSCI.4908-06.2007

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Cellular/Molecular
Munc13-1 C1 Domain Activation Lowers the Energy Barrier for Synaptic Vesicle Fusion

Jayeeta Basu,¹ Andrea Betz,² Nils Brose,² and Christian Rosenmund¹

¹Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and ²Max-Planck-Institute for Experimental Medicine, Department of Molecular Neurobiology, D-37075 Göttingen, Germany

Correspondence should be addressed to Dr. Christian Rosenmund, Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 833E, Houston, TX 77030. Email: rosenmun{at}bcm.tmc.edu

Synapses need to encode a wide dynamic range of action potential frequencies. Essential vesicle priming proteins of the Munc13 (mammalian Unc13) family play an important role in adapting vesicle supply to variable demand and thus influence short-term plasticity characteristics and synaptic function. Structure–function analyses of Munc13s have identified a "catalytic" C-terminal domain and several N-terminal modulatory domains, including a diacylglycerol/phorbol ester [4ß-phorbol-12, 13-dibutyrate (PDBu)] binding C1 domain. Although still allowing basal priming, a Munc13-1 C1 domain mutation (H567K) prevents PDBu induced potentiation of evoked transmitter release, leads to strong depression during trains of synaptic activity, and causes perinatal lethality in mice. To understand the mechanism of C1 domain-mediated modulation of Munc13 function, we examined how PDBu increases neurotransmitter release. Analyses of osmotically induced release as well as Ca²⁺ triggered and spontaneous release showed that PDBu increases the vesicular release rate without affecting the size of the readily releasable vesicle pool, linking C1 domain activation to a lowering of the energy barrier for vesicle fusion. PDBu binding-deficient mutant Munc13-1^H567K synapses mirrored the vesicular release properties of PDBu-potentiated wild-type synapses, indicating that Munc13-1^H567K is a gain-of-function mutant, which conformationally mimics the PDBu-activated state of Munc13-1. We propose a PKC analogous two-state model of regulation of Munc13s, in which the basal state of Munc13s is disinhibited by C1 domain activation into a state of facilitated vesicle release, regardless of whether the release is spontaneous or action potential triggered.

Key words: exocytosis; presynaptic mechanisms; release probability; phorbol; patch clamp; neurotransmission

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Received Nov. 10, 2006; revised Dec. 20, 2006; accepted Dec. 22, 2006.

Correspondence should be addressed to Dr. Christian Rosenmund, Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 833E, Houston, TX 77030. Email: rosenmun{at}bcm.tmc.edu

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