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The Journal of Neuroscience, January 3, 2007, 27(1):212-219; doi:10.1523/JNEUROSCI.4201-06.2007

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Cellular/Molecular
Potentiation of Exocytosis by Phospholipase C-Coupled G-Protein-Coupled Receptors Requires the Priming Protein Munc13-1

Claudia S. Bauer,¹ Robert J. Woolley,¹ Anja G. Teschemacher,² and Elizabeth P. Seward¹

¹Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom, and ²Department of Pharmacology, University of Bristol, Bristol BS3 1TD, United Kingdom

Correspondence should be addressed to Dr. Elizabeth P. Seward, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. Email: e.p.seward{at}sheffield.ac.uk

The vesicle priming protein Munc13-1 is regulated by diacylglycerol (DAG) and is therefore hypothesized to play a role in the control of neurotransmitter release by phospholipase C (PLC)-coupled receptors. We combined voltage-clamp recordings of voltage-gated Ca²⁺ channels (VGCCs) and high-resolution capacitance measurements to investigate the mechanism of receptor-mediated modulation of exocytosis in bovine chromaffin cells. Activation of endogenous H₁ G_q-protein-coupled receptors (G_qPCRs) by histamine potentiated stimulus-coupled secretion despite concurrently inhibiting Ca²⁺ influx through VGCCs. Histamine increased the size of the readily releasable pool of vesicles and in particular a subpool of fusion-competent vesicles localized in close proximity to VGCCs. Pharmacological characterization showed that potentiation of exocytosis depended on the activation of PLC but not protein kinase C. Overexpression of wild-type Munc13-1 by adenoviral infection had no effect on histamine-induced potentiation per se, whereas DAG-insensitive Munc13-1^H567K completely abolished it.

This is the first endogenous mammalian G_qPCR signaling pathway identified that engages Munc13-1 to increase stimulus-coupled secretion by recruiting vesicles to the immediately releasable pool. G_qPCRs are therefore able to control exocytosis at the level of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex formation to produce rapid, short-term potentiation of the secretory output of neurons and endocrine cells.

Key words: Munc13-1; chromaffin; exocytosis; GPCR; phospholipase C; calcium channels

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Received Sept. 26, 2006; revised Nov. 26, 2006; accepted Nov. 29, 2006.

Correspondence should be addressed to Dr. Elizabeth P. Seward, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. Email: e.p.seward{at}sheffield.ac.uk

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