Ca/calmodulin and Protein Kinase C (PKC) Reverse the Vesicle Fusion Arrest by Unmasking PIP

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2025 Feb 26

PMID 40009675

Authors

Houda Yasmine Ali Moussa

Kyung Chul Shin

Yongsoo Park

Affiliations

Soon will be listed here.

Abstract

Vesicle fusion is a key process in cellular communication and membrane trafficking. Soluble -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins drive vesicle fusion, and SNARE proteins seem to be partially assembled before fusion occurs. However, the molecular mechanisms of the vesicle fusion arrest and how vesicle fusion is rescued from the arrest remain not fully understood. We have previously shown that as a lipid catalyst, phosphatidylinositol 4,5-bisphosphate (PIP2) electrostatically triggers vesicle fusion by lowering the hydration energy, and masking PIP2 arrests vesicle fusion in a state of the partial SNARE assembly. In this study, we show that calmodulin and protein kinase C-epsilon unmask PIP2 through the dissociation of myristoylated alanine-rich C-kinase substrate from membranes and, thus, rescue basal fusion and potentiate synaptotagmin-1-mediated Ca-dependent vesicle fusion. We provide the model in which the arrest of vesicle fusion can be rescued by the unmasking of PIP2, a lipid catalyst for fusion.

References

Steinhardt R, Alderton J . Calmodulin confers calcium sensitivity on secretory exocytosis. Nature. 1982; 295(5845):154-5. DOI: 10.1038/295154a0. View

Quetglas S, Iborra C, Sasakawa N, De Haro L, Kumakura K, Sato K . Calmodulin and lipid binding to synaptobrevin regulates calcium-dependent exocytosis. EMBO J. 2002; 21(15):3970-9. PMC: 126150. DOI: 10.1093/emboj/cdf404. View

Papantoniou C, Laugks U, Betzin J, Capitanio C, Ferrero J, Sanchez-Prieto J . Munc13- and SNAP25-dependent molecular bridges play a key role in synaptic vesicle priming. Sci Adv. 2023; 9(25):eadf6222. PMC: 10284560. DOI: 10.1126/sciadv.adf6222. View

Ziemba B, Burke J, Masson G, Williams R, Falke J . Regulation of PI3K by PKC and MARCKS: Single-Molecule Analysis of a Reconstituted Signaling Pathway. Biophys J. 2016; 110(8):1811-1825. PMC: 4850241. DOI: 10.1016/j.bpj.2016.03.001. View

Arbuzova A, Wang J, Murray D, Jacob J, Cafiso D, McLaughlin S . Kinetics of interaction of the myristoylated alanine-rich C kinase substrate, membranes, and calmodulin. J Biol Chem. 1997; 272(43):27167-77. DOI: 10.1074/jbc.272.43.27167. View

Cheung W . Calmodulin plays a pivotal role in cellular regulation. Science. 1980; 207(4426):19-27. DOI: 10.1126/science.6243188. View

Park Y, Kim K . Dominant role of lipid rafts L-type calcium channel in activity-dependent potentiation of large dense-core vesicle exocytosis. J Neurochem. 2009; 110(2):520-9. DOI: 10.1111/j.1471-4159.2009.06148.x. View

Park Y, Hernandez J, van den Bogaart G, Ahmed S, Holt M, Riedel D . Controlling synaptotagmin activity by electrostatic screening. Nat Struct Mol Biol. 2012; 19(10):991-7. PMC: 3465474. DOI: 10.1038/nsmb.2375. View

Arbuzova A, Schmitz A, Vergeres G . Cross-talk unfolded: MARCKS proteins. Biochem J. 2002; 362(Pt 1):1-12. PMC: 1222354. DOI: 10.1042/0264-6021:3620001. View

10.

Jahn R, Cafiso D, Tamm L . Mechanisms of SNARE proteins in membrane fusion. Nat Rev Mol Cell Biol. 2023; 25(2):101-118. PMC: 11578640. DOI: 10.1038/s41580-023-00668-x. View

11.

De Camilli P, Jahn R . Pathways to regulated exocytosis in neurons. Annu Rev Physiol. 1990; 52:625-45. DOI: 10.1146/annurev.ph.52.030190.003205. View

12.

Sabatini B, Regehr W . Timing of neurotransmission at fast synapses in the mammalian brain. Nature. 1996; 384(6605):170-2. DOI: 10.1038/384170a0. View

13.

Llinas R, Steinberg I, Walton K . Relationship between presynaptic calcium current and postsynaptic potential in squid giant synapse. Biophys J. 1981; 33(3):323-51. PMC: 1327434. DOI: 10.1016/S0006-3495(81)84899-0. View

14.

Newton A . Regulation of protein kinase C. Curr Opin Cell Biol. 1997; 9(2):161-7. DOI: 10.1016/s0955-0674(97)80058-0. View

15.

Pobbati A, Stein A, Fasshauer D . N- to C-terminal SNARE complex assembly promotes rapid membrane fusion. Science. 2006; 313(5787):673-6. DOI: 10.1126/science.1129486. View

16.

Reim K, Mansour M, Varoqueaux F, McMahon H, Sudhof T, Brose N . Complexins regulate a late step in Ca2+-dependent neurotransmitter release. Cell. 2001; 104(1):71-81. DOI: 10.1016/s0092-8674(01)00192-1. View

17.

Suh B, Hille B . Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr Opin Neurobiol. 2005; 15(3):370-8. DOI: 10.1016/j.conb.2005.05.005. View

18.

Chamberlain L, Roth D, Morgan A, Burgoyne R . Distinct effects of alpha-SNAP, 14-3-3 proteins, and calmodulin on priming and triggering of regulated exocytosis. J Cell Biol. 1995; 130(5):1063-70. PMC: 2120563. DOI: 10.1083/jcb.130.5.1063. View

19.

Brown B, Walker S, Tomlinson S . Calcium calmodulin and hormone secretion. Clin Endocrinol (Oxf). 1985; 23(2):201-18. DOI: 10.1111/j.1365-2265.1985.tb00216.x. View

20.

Moussa H, Shin K, Ponraj J, Kim S, Ryu J, Mansour S . Requirement of Cholesterol for Calcium-Dependent Vesicle Fusion by Strengthening Synaptotagmin-1-Induced Membrane Bending. Adv Sci (Weinh). 2023; 10(15):e2206823. PMC: 10214243. DOI: 10.1002/advs.202206823. View