Regulated exocytosis is shared among many secretory cell types across the phylogenetic tree. Fusion of vesicle and plasma membranes is mediated by a highly conserved molecular machine comprising the SNARE proteins, whose function is fine- tuned through interaction with other proteins. One of these other proteins is complexin (CPX), a ~150-amino acid protein having four isoforms (I-IV), that binds stoichiometrically to the SNARE complex. The molecular mechanism of complexin action is controversial, with some evidence for a negative role - """"""""clamping"""""""" the SNARE complex and inhibiting exocytosis - and other evidence for a positive role, leading to enhanced exocytosis. We propose a systematic study of the function of CPX in mouse adrenal chromaffin cells and neuromuscular junction. These two model systems, one a hormone-secreting cell and one a synaptic preparation, have been used extensively to study calcium-dependent exocytosis. We have previously presented data supporting the hypothesis that CPXII plays a positive regulatory role in exocytosis in adrenal chromaffin cells, serving to prime vesicles. We propose to build on our previous work by testing the following specific hypotheses in chromaffin cells derived from CPXII knockout (CPX KO) mice: 1) CPXII must bind to the SNARE complex in order to facilitate priming. 2) Spontaneous exocytosis is not increased in knockout cells 3) CPXII facilitates molecular coupling of vesicles and calcium channels. 4) CPXII does not affect the Ca sensitivity of exocytosis. 5) CPXII must be phosphorylated to facilitate priming. We have preliminary evidence that CPXI also plays a positive role in the neuromuscular junction (NMJ). We will test the following hypothesis in a mouse CPXI KO model: 6) CPXI regulates the readily releasable pool in mouse NMJ. Knockout mice have been provided by our collaborator Nils Brose (Max Planck Institute, Germany). The multidisciplinary team includes Dr. Robert Chow, Dr. Jeannie Chen, Dr. Ralf Langen, and Dr. Chien-Ping Ko. Understanding CPX function could lead to new strategies to alter secretion rates to combat disease states or to improve biotechnological production of secreted products.

Public Health Relevance

The protein complexin controls how much cells can secrete. Understanding how it does this could lead to new strategies to alter secretion rates to combat disease states or to improve biotechnological production of secreted products.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Hagan, Ann A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Cho, Jung-Hwa; Swanson, Carter J; Chen, Jeannie et al. (2017) The GCaMP-R Family of Genetically Encoded Ratiometric Calcium Indicators. ACS Chem Biol 12:1066-1074
Okada, Alan K; Teranishi, Kazuki; Isas, J Mario et al. (2016) Diabetic Risk Factors Promote Islet Amyloid Polypeptide Misfolding by a Common, Membrane-mediated Mechanism. Sci Rep 6:31094
Weitz, Andrew C; Nanduri, Devyani; Behrend, Matthew R et al. (2015) Improving the spatial resolution of epiretinal implants by increasing stimulus pulse duration. Sci Transl Med 7:318ra203
Woolcott, Orison O; Richey, Joyce M; Kabir, Morvarid et al. (2015) High-fat diet-induced insulin resistance does not increase plasma anandamide levels or potentiate anandamide insulinotropic effect in isolated canine islets. PLoS One 10:e0123558
Weitz, Andrew C; Behrend, Matthew R; Ahuja, Ashish K et al. (2014) Interphase gap as a means to reduce electrical stimulation thresholds for epiretinal prostheses. J Neural Eng 11:016007
Hwang, Jae Youn; Lee, Nan Sook; Lee, Changyang et al. (2013) Investigating contactless high frequency ultrasound microbeam stimulation for determination of invasion potential of breast cancer cells. Biotechnol Bioeng 110:2697-705
Rohan, Joyce G; Citron, Y Rose; Durrell, Alec C et al. (2013) Light-triggered modulation of cellular electrical activity by ruthenium diimine nanoswitches. ACS Chem Neurosci 4:585-93
Weitz, Andrew C; Behrend, Matthew R; Lee, Nan Sook et al. (2013) Imaging the response of the retina to electrical stimulation with genetically encoded calcium indicators. J Neurophysiol 109:1979-88
Lin, Ming-Yi; Rohan, Joyce G; Cai, Haijiang et al. (2013) Complexin facilitates exocytosis and synchronizes vesicle release in two secretory model systems. J Physiol 591:2463-73
Woolcott, Orison O; Bergman, Richard N; Richey, Joyce M et al. (2012) Simplified method to isolate highly pure canine pancreatic islets. Pancreas 41:31-8

Showing the most recent 10 out of 13 publications