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Copine-6 Binds to Snares and Selectively Suppresses Spontaneous Neurotransmission

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Copine-6 Binds to Snares and Selectively Suppresses Spontaneous Neurotransmission This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular Copine-6 binds to SNAREs and selectively suppresses spontaneous neurotransmission Pei Liu1, Mikhail Khvotchev1, Ying C. Li1, Natali L. Chanaday1 and Ege T. Kavalali1,2 1Departments of Neuroscience 2Physiology, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA DOI: 10.1523/JNEUROSCI.0461-18.2018 Received: 20 February 2018 Revised: 11 May 2018 Accepted: 21 May 2018 Published: 25 May 2018 Author contributions: P.L., M.K., and E.T.K. designed research; P.L., M.K., Y.L., and N.C. performed research; P.L., M.K., Y.L., N.C., and E.T.K. analyzed data; P.L. and M.K. wrote the first draft of the paper; M.K., Y.L., N.C., and E.T.K. edited the paper; M.K. and E.T.K. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. We thank Brent Trauterman for his excellent technical assistance and other members of the Kavalali lab for their helpful comments. This work was supported by the NIH grant MH066198 (E.T.K). Corresponding author: Ege T. Kavalali, Ph.D., Department of Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9111, Phone: 214-648-1682, E-mail: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.0461-18.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors 1 Copine-6 binds to SNAREs and selectively suppresses spontaneous neurotransmission 2 Pei Liu1, Mikhail Khvotchev1, Ying C. Li1, Natali L. Chanaday1, and Ege T. Kavalali1,2 3 1Departments of Neuroscience and 2Physiology, UT Southwestern Medical Center, Dallas, TX 75390- 4 9111, USA 5 Abbreviated Title: Copine-6 and spontaneous neurotransmission 6 Corresponding author: Ege T. Kavalali, Ph.D. 7 Department of Neuroscience 8 UT Southwestern Medical Center 9 5323 Harry Hines Blvd. 10 Dallas, TX 75390-9111 11 Phone: 214-648-1682 12 E-mail: [email protected] 13 14 Number of pages: 21 15 Number of figures: 5 16 Number of words in Abstract: 150 17 Number of words in Introduction: 654 18 Number of words in Discussion: 937 19 20 Conflicts of Interest: The authors declare no competing financial interests. 21 22 Acknowledgements: We thank Brent Trauterman for his excellent technical assistance and other 23 members of the Kavalali lab for their helpful comments. This work was supported by the NIH grant 24 MH066198 (E.T.K). 25 26 27 28 29 30 31 32 33 34 1 35 Abstract 36 Recent studies suggest that spontaneous and action potential evoked neurotransmitter release 37 processes are independently regulated. However, the mechanisms that uncouple the two forms of 38 neurotransmission remain unclear. In cultured mouse and rat neurons, we show that the two C2-domain 39 containing protein copine-6 is localized to presynaptic terminals and binds to synaptobrevin2 as well as 40 other SNARE proteins in a Ca2+-dependent manner. Ca2+-dependent interaction of copine-6 with 41 synaptobrevin2 selectively suppresses spontaneous neurotransmission in a reaction that requires the 42 tandem tryptophan residues at the C-terminal region of synaptobrevin2. Accordingly, copine-6 loss-of- 43 function augmented presynaptic Ca2+ elevation-mediated neurotransmitter release. Intracellular Ca2+ 44 chelation, on the other hand, occluded copine-6-mediated suppression of release. We also evaluated 45 the molecular specificity of the copine-6-dependent regulation of spontaneous release and found that 46 overexpression of copine-6 did not suppress spontaneous release in synaptobrevin2-deficient neurons. 47 Taken together, these results suggest that copine-6 acts as a specific Ca2+-dependent suppressor of 48 spontaneous neurotransmission. 49 50 Significance Statement 51 Synaptic transmission occurs both in response to presynaptic action potentials and spontaneously, in 52 the absence of stimulation. Currently, much more is understood about the mechanisms underlying 53 action potential-evoked neurotransmission compared to spontaneous release. However, recent studies 54 have shown selective modulation of spontaneous neurotransmission process by several 55 neuromodulators suggesting specific molecular regulation of spontaneous release. In this study, we 56 identify copine-6 as a specific regulator of spontaneous neurotransmission. By both gain-of-function and 57 loss-of-function experiments, we show that copine-6 functions as a Ca2+-dependent suppressor of 58 spontaneous release. These results further elucidate the mechanisms underlying differential regulation 59 of evoked and spontaneous neurotransmitter release. 60 2 61 Introduction 62 Spontaneous neurotransmitter release is a key feature of presynaptic terminals (Fatt and Katz, 1952). At 63 synapses, most Ca2+-dependent action potential evoked neurotransmitter release and a large fraction of 64 spontaneous release events are mediated by the canonical synaptic SNARE (Soluble N-ethylmaleimide- 65 sensitive factor Attachment Protein Receptor) complex composed of synaptobrevin2 (syb2, also called 66 VAMP2) on the synaptic vesicle and syntaxin1 and SNAP-25, both on the synaptic plasma membrane 67 (Sudhof and Rothman, 2009). Although, syb2 is the most abundant vesicle associated SNARE and is 68 essential for fast synchronous neurotransmission (Schoch et al., 2001; Takamori et al., 2006), recent 69 evidence suggests that a fraction of spontaneous neurotransmitter release events is mediated by 70 alternative vesicular SNARE proteins such as vti1a, VAMP7 and VAMP4 (Bal et al., 2013; Hua et al., 2011; 71 Kavalali, 2015; Raingo et al., 2012; Ramirez et al., 2012). These alternative SNAREs may molecularly 72 identify functionally distinct synaptic vesicle populations and render these vesicles insensitive to rapid 73 Ca2+ transients but nevertheless enable them to fuse spontaneously or asynchronously in response to 74 slow fluctuations in baseline Ca2+ levels (Crawford and Kavalali, 2015). Moreover, there is evidence that 75 these alternative SNARE molecules may be enriched in synaptic vesicles that are retrieved 76 spontaneously (Revelo et al., 2014). However, despite the evidence in support of a key role for these 77 alternative SNAREs in spontaneous and asynchronous release processes, in mammalian central synapses 78 a substantial fraction (90-70%) of spontaneous release events are carried out by the canonical vesicular 79 SNARE syb2 (Schoch et al., 2001; Kaeser and Regehr, 2014; Schneggenburger and Rosenmund, 2015). 80 Therefore, findings on the role of alternative SNARE molecules in neurotransmitter release do not fully 81 explain why syb2-driven spontaneous release events are segregated from syb2-mediated evoked release 82 events as suggested by earlier studies (Sara et al., 2005; Atasoy et al., 2008; Chung et al., 2010; Fredj and 83 Burrone, 2009; Leitz and Kavalali, 2014). 84 In this study, we have identified copine-6, a two C2 domain containing cytosolic protein, as a Ca2+- 85 dependent binding partner for syb2 as well as other SNAREs. Copine-6 belongs to an evolutionarily 86 conserved family of proteins (Copines) that bind negatively charged lipids and other proteins in a Ca2+ 87 regulated manner (Tomsig and Creutz, 2002). There are 9 copine genes discovered in human and 88 mammals. Copines share a highly conserved architecture containing a pair of tandem C2 domains (C2A 89 and C2B) in the N-terminus and a domain related to integrin A domain and a von Willebrand factor 90 (vWA) domain interspersed by short linker sequences (Fig. 1A) (Creutz et al., 1998). Similar to 91 synaptotagmins and protein kinase C (PKC), the C2 domains of copines bind negatively charged 92 phospholipids in the presence of Ca2+ with micromolar affinity (~1-10 μM). The vWA domain of copines 93 also binds to multiple proteins in vitro with unclear functional significance (Tomsig et al., 2003). Among 94 copine protein family, copine-6 is also described as N-Copine as it is highly enriched in postnatal brain, 95 especially in somatodendritic domains of hippocampus and olfactory bulb (Nakayama et al., 1999; 96 Nakayama et al., 1998). It has been shown that copine-6 expression increased up to 25-fold during 97 maturation in developing axonal projections (Yamatani et al., 2010) and its mRNA level was found to be 98 up-regulated upon kainate injection or high frequency electrical stimulation that induces LTP in the 99 hippocampus (Nakayama et al., 1998). Recent findings indicate that copine-6 may also play a key role in 100 dendritic spine morphology through interactions with brain-derived neurotrophic factor (BDNF) 101 signaling (Burk et al., 2017). Here, we manipulated copine-6 expression in hippocampal neurons and 3 102 found that overexpression of copine-6 resulted in a decrease in the frequency of spontaneous miniature 103 postsynaptic currents, while knockdown of copine-6 increased their frequency. This regulation was 104 presynaptic and specific to spontaneous events as evoked neurotransmission was largely unaffected by 105 the same manipulations. Furthermore, we demonstrated that this regulation requires copine-6’s 106 interaction with the key SNARE component syb2. Our results support the notion that the copine-6 107 selectively regulates spontaneous neurotransmission within central synapses. 108 Materials
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