FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2022871070> ?p ?o ?g. }

• W2022871070 endingPage "567" @default.
• W2022871070 startingPage "566" @default.
• W2022871070 abstract "A new study by Yao et al. in the current issue of Cell proposes that a novel vesicular protein, dubbed Flower, regulates endocytosis by controlling presynaptic Ca2+ levels. This finding is intriguing not only for its implications for vesicle cycling, but also for the multitude of Ca2+-dependent processes at play in presynaptic nerve terminals. A new study by Yao et al. in the current issue of Cell proposes that a novel vesicular protein, dubbed Flower, regulates endocytosis by controlling presynaptic Ca2+ levels. This finding is intriguing not only for its implications for vesicle cycling, but also for the multitude of Ca2+-dependent processes at play in presynaptic nerve terminals. It is well established that activation of presynaptic voltage-gated Ca2+ channels triggers the fusion of synaptic vesicles with the plasma membrane, leading to release of neurotransmitter. Lately, much attention has turned to the role of Ca2+ on the other side of the synaptic vesicle cycle, in which vesicular membrane and protein are retrieved from the plasma membrane by the process of endocytosis. Although the mechanistic details of endocytosis are still being clarified, it is clear from studies using diverse experimental preparations and paradigms that endocytosis, like exocytosis, is regulated by Ca2+ (Ceccarelli and Hurlbut, 1980Ceccarelli B. Hurlbut W.P. J. Cell Biol. 1980; 87: 297-303Crossref PubMed Scopus (179) Google Scholar, Sankaranarayanan and Ryan, 2001Sankaranarayanan S. Ryan T.A. Nat. Neurosci. 2001; 4: 129-136Crossref PubMed Scopus (234) Google Scholar, Wu et al., 2009Wu X.S. McNeil B.D. Xu J. Fan J. Xue L. Melicoff E. Adachi R. Bai L. Wu L.G. Nat. Neurosci. 2009; 12: 1003-1010Crossref PubMed Scopus (162) Google Scholar). Where exactly does the Ca2+ that modulates endocytosis come from? This unresolved issue has important implications for the relationship between exocytosis and endocytosis. One possibility is that endocytic processes respond to Ca2+ entry through the same Ca2+ channels that trigger exocytosis. However, exocytosis and endocytosis do not necessarily occur at the same site, they have different time courses, and they may have different dependencies on Ca2+ concentration (Heuser and Reese, 1973Heuser J.E. Reese T.S. J. Cell Biol. 1973; 57: 315-344Crossref PubMed Scopus (1566) Google Scholar, Hosoi et al., 2009Hosoi N. Holt M. Sakaba T. Neuron. 2009; 63: 216-229Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, Wu et al., 2007Wu L.G. Ryan T.A. Lagnado L. J. Neurosci. 2007; 27: 11793-11802Crossref PubMed Scopus (82) Google Scholar). It might be expected then that having different sources of Ca2+ could permit finer control over distinct aspects of the vesicle cycle. But, if there are distinct Ca2+ signals, how can they be coordinated to support the balance between exocytosis and endocytosis necessary for maintained synaptic transmission? In the current issue of Cell, Yao et al., 2009Yao C.K. Lin Y.Q. Ly C.V. Ohyama T. Haueter C.M. Mosieenkiova-Bell V.Y. Wensel T.G. Bellen H.J. Cell. 2009; 138: in pressAbstract Full Text Full Text PDF Scopus (100) Google Scholar identify a novel Ca2+ channel localized to synaptic vesicles. They propose that the insertion of this channel in the plasma membrane provides a source of Ca2+ that selectively regulates endocytosis, but not exocytosis, and could provide a critical link between these different phases of the synaptic vesicle cycle. The new work by Yao et al. arose from a forward genetic screen for synaptic transmission mutants in Drosophila. Out of a number of mutations identified in this screen, two mapped to a gene with previously unknown function that the authors named “flower,” since a phenotypic consequence of the mutations was the breakup of neuromuscular junctions (NMJs) into florets of tiny, synaptic boutons. Using several immunolabeling approaches, Yao et al. demonstrated that the B isoform of the Flower protein, the only one of three splice variants expressed in the nervous system, is primarily associated with synaptic vesicles with some additional expression at the presynaptic membrane. The vesicular localization of Flower suggested to Yao et al. a potential role in synaptic vesicle trafficking. Indeed, anatomical and functional analysis of the mutants revealed multiple phenotypic features reminiscent of previously identified mutants deficient in synaptic vesicle endocytosis including larger synaptic vesicles, an increase in the appearance of endocytic intermediates at terminals, and greater depression of excitatory junction potential amplitudes recorded at the NMJ at moderate stimulus frequencies. Compared to those of control flies, flower mutant NMJ terminals also exhibited less depolarization-induced uptake of the styryl dye FM1-43, which fluorescently labels endocytosed membranes, consistent with a deficit in endocytosis. What is Flower doing on vesicles and how does its function contribute to endocytosis? The flower gene is evolutionarily conserved from worms to humans, and Yao et al. noticed that the highest amino acid sequence homology between species occurs within the predicted transmembrane (TM) regions of the Flower protein (three or four TM domains were predicted from the primary amino acid sequence). The authors were particularly intrigued by a conserved glutamate-alanine-proline (EAP) sequence in the second predicted TM domain (TM2) of all Flower homologs because Ca2+ selectivity in voltage-gated Ca2+ channels is thought to rely upon conserved glutamate or aspartate residues in the pore region of these channels. Further, similar amino acid sequences were observed in the ion selectivity region of the Ca2+-permeable TRPV5 and TRPV6 channels and the EAP-containing region within TM2 of Flower. Although the predicted membrane topology of Flower is unlike that of voltage-gated channels (four repeated domains of six TM regions) or TRPV5 and TRPV6 channels (six TM regions in each subunit), the authors note that examples of four-TM-domain proteins that form calcium channels do exist. Thus, Yao et al. hypothesize that Flower forms a Ca2+-permeable channel in the synaptic vesicle membrane. Yao et al. could not achieve membrane expression of Flower in standard heterologous expression systems and were therefore not able to directly test the possible Ca2+ permeability of Flower using electrophysiology. The authors instead examined this issue by expressing the B isoform of Flower in Drosophila salivary gland cells, which are secretory cells that do not normally express Flower. Flower expressed in salivary gland cells localized to the cell surface and resulted in the gradual intracellular accumulation of Ca2+, as assessed by Ca2+ imaging. Importantly, mutation of the predicted second TM glutamate residue to an uncharged glutamine residue reduced Ca2+ accumulation to baseline levels. To rule out the possibility that Flower expression was gating Ca2+ permeability of a different protein endogenous to salivary gland cells, Yao et al. also reconstituted purified Flower protein into proteoliposomes. Consistent with the formation of a Ca2+-permeable channel, liposomes containing Flower exhibited significantly more uptake of radioactively labeled Ca2+ ions compared to empty liposomes. Finally, the authors reasoned that if Flower forms a Ca2+channel, its expression at the presynaptic membrane, which they had previously established, might measurably alter presynaptic resting Ca2+ levels. In fact, when they measured resting Ca2+ levels in NMJ boutons, they observed a significant decrease in Ca2+ in flower mutants compared to controls that was at least partially rescued by reintroduction of wild-type Flower into the mutants. When these lines of evidence for the Ca2+ permeability of Flower are considered together, it seems likely that this protein represents a novel route for Ca2+ entry to the presynaptic terminal. Yao et al. conclude that Flower forms Ca2+ channels in vesicle membranes and that their presence regulates endocytosis. The authors suggest a model in which Flower is associated with synaptic vesicles at rest, but after insertion into the presynaptic plasma membrane upon full-fusion exocytosis, Ca2+ influx through Flower contributes to the Ca2+ signal mediating endocytic reuptake of vesicular membrane (including Flower itself) (see Figure 7E of Yao et al., 2009Yao C.K. Lin Y.Q. Ly C.V. Ohyama T. Haueter C.M. Mosieenkiova-Bell V.Y. Wensel T.G. Bellen H.J. Cell. 2009; 138: in pressAbstract Full Text Full Text PDF Scopus (100) Google Scholar). Hence, Flower is a channel in effect “gated” by the synaptic vesicle cycle. This self-regulatory mechanism presents a conceptually satisfying solution to the problem of maintaining a balance between exocytosis and endocytosis at the synapse; with increasing levels of exocytosis, more Flower is inserted into the synaptic membrane and the ensuing increase in Ca2+ triggers higher levels of endocytosis. If Flower selectively associates with vesicular proteins, it could even enhance the efficiency of synaptic vesicle recycling by providing a local signal for the selective reuptake of critical vesicular constituents. It should be mentioned that Yao et al. did not explicitly link the Ca2+ channel behavior of Flower to a direct role in endocytosis. Their data leaves open the possibility that disruption of a separate function of Flower, distinct from or in addition to its ability to conduct Ca2+ ions, may account for the endocytosis defects in flower mutants. This possibility could potentially be addressed by assessing the effect of introducing Flower with the TM2 domain glutamate-to-glutamine mutation (which the authors showed abolishes Ca2+ permeability) into flower mutant flies. Since this point mutation should affect Ca2+ entry through Flower while leaving intact other potential functional domains, the prediction would be that the endocytosis deficiencies of flower mutants would not be rescued in such an experiment. Nevertheless, the discovery of a novel presynaptic Ca2+ source has significant ramifications for the regulation of presynaptic Ca2+ levels that extend beyond synaptic vesicle endocytosis. The resting [Ca2+]i of synaptic terminals is a critical determinant of several fundamental presynaptic properties including the probability of neurotransmitter release and the mobilization of vesicles between reserve and readily-releasable pools (Neher and Sakaba, 2008Neher E. Sakaba T. Neuron. 2008; 59: 861-872Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar). Even small changes in resting Ca2+ levels may have significant effects on presynaptic function. For example, in some mammalian nerve terminals, vesicle release probability is enhanced by small depolarizations that elicit increases in background presynaptic [Ca2+] of less than 100 nM (Awatramani et al., 2005Awatramani G.B. Price G.D. Trussell L.O. Neuron. 2005; 48: 109-121Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). Since the membrane distribution of Flower is proposed to depend on the recent history of exocytosis, this protein could provide a means to regulate resting presynaptic [Ca2+]i and, accordingly, presynaptic function in relation to recent patterns of activity. Because the suggestion that Flower is a novel Ca2+ source has many potential consequences for synaptic transmission, it will be critical to obtain direct evidence that it is in fact a Ca2+ channel. Thus, future studies will need to achieve successful membrane expression of Flower in a heterologous system amenable to patch-clamp analysis. Likewise, clear demonstration that Flower is in fact inserted into the presynaptic membrane and alters terminal Ca2+ levels upon exocytosis would further cement an important role for Flower in presynaptic physiology. Beyond clarifying these issues, numerous additional questions will blossom forth from the study of Yao et al., as befits the first description of a new synaptic protein. Most non-Drosophila neurobiologists will ask about the targeting and function of Flower homologs in other species. In regards to its contribution at synapses, how does Ca2+ flux through Flower compare to that mediated by other sources such as voltage-gated channels, and do their relative contributions change under specific conditions? Is Flower activity selectively associated with specific presynaptic spike patterns? Since kinetically distinct modes of endocytosis appear to have different requirements for Ca2+ (Wu et al., 2009Wu X.S. McNeil B.D. Xu J. Fan J. Xue L. Melicoff E. Adachi R. Bai L. Wu L.G. Nat. Neurosci. 2009; 12: 1003-1010Crossref PubMed Scopus (162) Google Scholar), answering these questions may shed light on regulatory mechanisms underlying different endocytic pathways. If the proposed role for Flower proves ubiquitous, what would this mean for “kiss-and-run” exocytosis, in which the protein would have no access to plasma membrane? The discovery of Flower by Yao et al. provides an exciting new perspective on endocytosis. Further study may bear unexpected fruit for other aspects of presynaptic function as well." @default.
• W2022871070 created "2016-06-24" @default.
• W2022871070 creator A5022050123 @default.
• W2022871070 creator A5027038334 @default.
• W2022871070 date "2009-09-01" @default.
• W2022871070 modified "2023-09-27" @default.
• W2022871070 title "A New Ion Channel Blooms at the Synapse" @default.
• W2022871070 cites W1562455864 @default.
• W2022871070 cites W1989650926 @default.
• W2022871070 cites W1998550403 @default.
• W2022871070 cites W2010482889 @default.
• W2022871070 cites W2045202254 @default.
• W2022871070 cites W2063618791 @default.
• W2022871070 cites W2095352259 @default.
• W2022871070 cites W2145527534 @default.
• W2022871070 cites W2172095199 @default.
• W2022871070 doi "https://doi.org/10.1016/j.neuron.2009.08.031" @default.
• W2022871070 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19755100" @default.
• W2022871070 hasPublicationYear "2009" @default.
• W2022871070 type Work @default.
• W2022871070 sameAs 2022871070 @default.
• W2022871070 citedByCount "3" @default.
• W2022871070 countsByYear W20228710702012 @default.
• W2022871070 countsByYear W20228710702017 @default.
• W2022871070 crossrefType "journal-article" @default.
• W2022871070 hasAuthorship W2022871070A5022050123 @default.
• W2022871070 hasAuthorship W2022871070A5027038334 @default.
• W2022871070 hasBestOaLocation W20228710701 @default.
• W2022871070 hasConcept C127162648 @default.
• W2022871070 hasConcept C127445978 @default.
• W2022871070 hasConcept C15744967 @default.
• W2022871070 hasConcept C169760540 @default.
• W2022871070 hasConcept C170493617 @default.
• W2022871070 hasConcept C2909795284 @default.
• W2022871070 hasConcept C41008148 @default.
• W2022871070 hasConcept C50254741 @default.
• W2022871070 hasConcept C54355233 @default.
• W2022871070 hasConcept C76155785 @default.
• W2022871070 hasConcept C86803240 @default.
• W2022871070 hasConceptScore W2022871070C127162648 @default.
• W2022871070 hasConceptScore W2022871070C127445978 @default.
• W2022871070 hasConceptScore W2022871070C15744967 @default.
• W2022871070 hasConceptScore W2022871070C169760540 @default.
• W2022871070 hasConceptScore W2022871070C170493617 @default.
• W2022871070 hasConceptScore W2022871070C2909795284 @default.
• W2022871070 hasConceptScore W2022871070C41008148 @default.
• W2022871070 hasConceptScore W2022871070C50254741 @default.
• W2022871070 hasConceptScore W2022871070C54355233 @default.
• W2022871070 hasConceptScore W2022871070C76155785 @default.
• W2022871070 hasConceptScore W2022871070C86803240 @default.
• W2022871070 hasIssue "5" @default.
• W2022871070 hasLocation W20228710701 @default.
• W2022871070 hasLocation W20228710702 @default.
• W2022871070 hasOpenAccess W2022871070 @default.
• W2022871070 hasPrimaryLocation W20228710701 @default.
• W2022871070 hasRelatedWork W2045350046 @default.
• W2022871070 hasRelatedWork W2055544911 @default.
• W2022871070 hasRelatedWork W2067100363 @default.
• W2022871070 hasRelatedWork W2131674028 @default.
• W2022871070 hasRelatedWork W2148673800 @default.
• W2022871070 hasRelatedWork W2152284832 @default.
• W2022871070 hasRelatedWork W2417250347 @default.
• W2022871070 hasRelatedWork W2529699144 @default.
• W2022871070 hasRelatedWork W4368358747 @default.
• W2022871070 hasRelatedWork W6459375 @default.
• W2022871070 hasVolume "63" @default.
• W2022871070 isParatext "false" @default.
• W2022871070 isRetracted "false" @default.
• W2022871070 magId "2022871070" @default.
• W2022871070 workType "article" @default.