Minor Differences in the Molecular Machinery Mediating Regulated Membrane Fusion Has Major Impact on Metabolic Health

Overview

Journal Adipocyte

Specialties Cell Biology
Endocrinology
Physiology

Date 2016 Sep 13

PMID 27617177

Citations 3

Authors

Ismael Valladolid-Acebes

Teresa Daraio

Kerstin Brismar

Tomas Hokfelt

Christina Bark

Affiliations

Soon will be listed here.

Abstract

The exocytosis of signaling molecules from neuronal, neuroendocrine and endocrine cells is regulated by membrane fusion involving SNAP-25 and associated SNARE proteins. The importance of this process for metabolic control recently became evident by studies of mouse mutants genetically engineered to only express one of 2 closely related, alternatively-spliced variants of SNAP-25. The results showed that even minor differences in the function of proteins regulating exocytosis are sufficient to provoke metabolic disease, including hyperglycaemia, liver steatosis, adipocyte hypertrophy and obesity. Thus, an imbalance in the dynamics of hormonal and/or neurotransmitter release can cause obesity and type 2 diabetes. This recent discovery highlights the fact that metabolic health requires a perfectly operating interplay between the SNARE protein machinery in excitable cells and the organs responding to these messengers.

Citing Articles

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

Hao X, Zhu B, Yang P, Dong D, Sahbaie P, Oliver P Biochim Biophys Acta Mol Basis Dis. 2021; 1868(2):166304.

PMID: 34826585 PMC: 8759409. DOI: 10.1016/j.bbadis.2021.166304.

SNAP-25 isoforms differentially regulate synaptic transmission and long-term synaptic plasticity at central synapses.

Irfan M, Gopaul K, Miry O, Hokfelt T, Stanton P, Bark C Sci Rep. 2019; 9(1):6403.

PMID: 31024034 PMC: 6484009. DOI: 10.1038/s41598-019-42833-3.

The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes.

McCammon J, Blaker-Lee A, Chen X, Sive H Hum Mol Genet. 2017; 26(19):3699-3712.

PMID: 28934389 PMC: 5886277. DOI: 10.1093/hmg/ddx255.

References

Kim J, Biederman J, Arbeitman L, Fagerness J, Doyle A, Petty C . Investigation of variation in SNAP-25 and ADHD and relationship to co-morbid major depressive disorder. Am J Med Genet B Neuropsychiatr Genet. 2007; 144B(6):781-90. DOI: 10.1002/ajmg.b.30522. View

Valladolid-Acebes I, Daraio T, Brismar K, Harkany T, Ogren S, Hokfelt T . Replacing SNAP-25b with SNAP-25a expression results in metabolic disease. Proc Natl Acad Sci U S A. 2015; 112(31):E4326-35. PMC: 4534236. DOI: 10.1073/pnas.1511951112. View

Kustanovich V, Merriman B, McGough J, McCracken J, Smalley S, Nelson S . Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder. Mol Psychiatry. 2003; 8(3):309-15. DOI: 10.1038/sj.mp.4001247. View

Carr K . Nobel goes to discoverers of 'split genes'. Nature. 1993; 365(6447):597. DOI: 10.1038/365597a0. View

Long Y, Zierath J . AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006; 116(7):1776-83. PMC: 1483147. DOI: 10.1172/JCI29044. View

Musil R, Spellmann I, Riedel M, Dehning S, Douhet A, Maino K . SNAP-25 gene polymorphisms and weight gain in schizophrenic patients. J Psychiatr Res. 2008; 42(12):963-70. DOI: 10.1016/j.jpsychires.2007.11.003. View

Soderqvist S, McNab F, Peyrard-Janvid M, Matsson H, Humphreys K, Kere J . The SNAP25 gene is linked to working memory capacity and maturation of the posterior cingulate cortex during childhood. Biol Psychiatry. 2010; 68(12):1120-5. DOI: 10.1016/j.biopsych.2010.07.036. View

Barr C, Feng Y, Wigg K, Bloom S, Roberts W, Malone M . Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry. 2000; 5(4):405-9. DOI: 10.1038/sj.mp.4000733. View

Johansson J, Ericsson J, Janson J, Beraki S, Stanic D, Mandic S . An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function. PLoS Genet. 2008; 4(11):e1000278. PMC: 2581893. DOI: 10.1371/journal.pgen.1000278. View

10.

Sutton R, Fasshauer D, Jahn R, Brunger A . Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature. 1998; 395(6700):347-53. DOI: 10.1038/26412. View

11.

Bark C, Bellinger F, Kaushal A, Mathews J, Donald Partridge L, Wilson M . Developmentally regulated switch in alternatively spliced SNAP-25 isoforms alters facilitation of synaptic transmission. J Neurosci. 2004; 24(40):8796-805. PMC: 6729955. DOI: 10.1523/JNEUROSCI.1940-04.2004. View

12.

Goldlust I, Hermetz K, Catalano L, Barfield R, Cozad R, Wynn G . Mouse model implicates GNB3 duplication in a childhood obesity syndrome. Proc Natl Acad Sci U S A. 2013; 110(37):14990-4. PMC: 3773733. DOI: 10.1073/pnas.1305999110. View

13.

Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M . Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population. Mol Psychiatry. 2002; 7(8):913-7. DOI: 10.1038/sj.mp.4001092. View

14.

Al-Daghri N, Costa A, Alokail M, Zanzottera M, Alenad A, Mohammed A . Synaptosomal Protein of 25 kDa (Snap25) Polymorphisms Associated with Glycemic Parameters in Type 2 Diabetes Patients. J Diabetes Res. 2016; 2016:8943092. PMC: 4686705. DOI: 10.1155/2016/8943092. View

15.

Ford E, Giles W, Dietz W . Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002; 287(3):356-9. DOI: 10.1001/jama.287.3.356. View

16.

Tsunoda K, Sanke T, Nakagawa T, Furuta H, Nanjo K . Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic patients. Diabetologia. 2001; 44(11):2092-7. DOI: 10.1007/s001250100015. View

17.

Muller T, Tschop M . Ghrelin - a key pleiotropic hormone-regulating systemic energy metabolism. Endocr Dev. 2013; 25:91-100. DOI: 10.1159/000346590. View

18.

Steinbusch L, Labouebe G, Thorens B . Brain glucose sensing in homeostatic and hedonic regulation. Trends Endocrinol Metab. 2015; 26(9):455-66. DOI: 10.1016/j.tem.2015.06.005. View

19.

Gosso M, de Geus E, Polderman T, Boomsma D, Heutink P, Posthuma D . Common variants underlying cognitive ability: further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts. Genes Brain Behav. 2007; 7(3):355-64. DOI: 10.1111/j.1601-183X.2007.00359.x. View

20.

Olson T, Terzic A . Human K(ATP) channelopathies: diseases of metabolic homeostasis. Pflugers Arch. 2009; 460(2):295-306. PMC: 2883927. DOI: 10.1007/s00424-009-0771-y. View