nach oben

Erschienen in:

01.02.2015 | Article

Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells

verfasst von: Haiqiang Dou, Changhe Wang, Xi Wu, Lijun Yao, Xiaoyu Zhang, Sasa Teng, Huadong Xu, Bin Liu, Qihui Wu, Quanfeng Zhang, Meiqin Hu, Yeshi Wang, Li Wang, Yi Wu, Shujiang Shang, Xinjiang Kang, Lianghong Zheng, Jin Zhang, Matthieu Raoux, Jochen Lang, Qing Li, Jing Su, Xiao Yu, Liangyi Chen, Zhuan Zhou

Erschienen in: Diabetologia | Ausgabe 2/2015

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Insulin is a key metabolic regulator in health and diabetes. In pancreatic beta cells, insulin release is regulated by the major second messengers Ca²⁺ and cAMP: exocytosis is triggered by Ca²⁺ and mediated by the cAMP/protein kinase A (PKA) signalling pathway. However, the causal link between these two processes in primary beta cells remains undefined.

Methods

Time-resolved confocal imaging of fluorescence resonance energy transfer signals was performed to visualise PKA activity, and combined membrane capacitance recordings were used to monitor insulin secretion from patch-clamped rat beta cells.

Results

Membrane depolarisation-induced Ca²⁺ influx caused an increase in cytosolic PKA activity via activating a Ca²⁺-sensitive adenylyl cyclase 8 (ADCY8) subpool. Glucose stimulation triggered coupled Ca²⁺ oscillations and PKA activation. ADCY8 knockdown significantly reduced the level of depolarisation-evoked PKA activation and impaired replenishment of the readily releasable vesicle pool. Pharmacological inhibition of PKA by two inhibitors reduced depolarisation-induced PKA activation to a similar extent and reduced the capacity for sustained vesicle exocytosis and insulin release.

Conclusions/interpretation

Our findings suggest that depolarisation-induced Ca²⁺ influx plays dual roles in regulating exocytosis in rat pancreatic beta cells by triggering vesicle fusion and replenishing the vesicle pool to support sustained insulin release. Therefore, Ca²⁺ influx may be important for glucose-stimulated insulin secretion.

Nur mit Berechtigung zugänglich

Tarasov AI, Semplici F, Ravier MA et al (2012) The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. Plos One 7:e39722

Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the beta cell: the last ten years. Cell 148:1160–1171PubMedCrossRef

Zhou Z, Misler S (1996) Amperometric detection of quantal secretion from patch-clamped rat pancreatic beta-cells. J Biol Chem 271:270–277PubMedCrossRef

Renstrom E, Eliasson L, Rorsman P (1997) Protein kinase A-dependent and -independent stimulation of exocytosis by cAMP in mouse pancreatic B cells. J Physiol 502(Pt 1):105–118PubMedCentralPubMedCrossRef

Eliasson L, Ma X, Renstrom E et al (2003) SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B cells. J Gen Physiol 121:181–197PubMedCentralPubMedCrossRef

Shibasaki T, Takahashi H, Miki T et al (2007) Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. Proc Natl Acad Sci U S A 104:19333–19338PubMedCentralPubMedCrossRef

Gremlich S, Porret A, Hani EH et al (1995) Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 44:1202–1208PubMedCrossRef

Thorens B (1992) Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A 89:8641–8645PubMedCentralPubMedCrossRef

Grill V, Cerasi E (1973) Activation by glucose of adenyl cyclase in pancreatic islets of the rat. FEBS Lett 33:311–314PubMedCrossRef

10.

Ramos LS, Zippin JH, Kamenetsky M, Buck J, Levin LR (2008) Glucose and GLP-1 stimulate cAMP production via distinct adenylyl cyclases in INS-1E insulinoma cells. J Gen Physiol 132:329–338PubMedCentralPubMedCrossRef

11.

Dyachok O, Idevall-Hagren O, Sagetorp J et al (2008) Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab 8:26–37PubMedCrossRef

12.

Hodson DJ, Mitchell RK, Marselli L et al (2014) ADCY5 couples glucose to insulin secretion in human islets. Diabetes 63:3009–3021PubMedCrossRef

13.

Delmeire D, Flamez D, Hinke SA, Cali JJ, Pipeleers D, Schuit F (2003) Type VIII adenylyl cyclase in rat beta cells: coincidence signal detector/generator for glucose and GLP-1. Diabetologia 46:1383–1393PubMedCrossRef

14.

Landa LR Jr, Harbeck M, Kaihara K et al (2005) Interplay of Ca2+ and cAMP signaling in the insulin-secreting MIN6 beta-cell line. J Biol Chem 280:31294–31302PubMedCentralPubMedCrossRef

15.

Ni Q, Ganesan A, Aye-Han NN et al (2011) Signaling diversity of PKA achieved via a Ca2+-cAMP-PKA oscillatory circuit. Nat Chem Biol 7:34–40PubMedCentralPubMedCrossRef

16.

De Marinis YZ, Salehi A, Ward CE et al (2010) GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab 11:543–553PubMedCrossRef

17.

Kamp TJ, Hell JW (2000) Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ Res 87:1095–1102PubMedCrossRef

18.

Kang G, Chepurny OG, Rindler MJ et al (2005) A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells. J Physiol 566:173–188PubMedCentralPubMedCrossRef

19.

Dyachok O, Gylfe E (2004) Ca(2+)-induced Ca(2+) release via inositol 1,4,5-trisphosphate receptors is amplified by protein kinase A and triggers exocytosis in pancreatic beta-cells. J Biol Chem 279:45455–45461PubMedCrossRef

20.

Idevall-Hagren O, Barg S, Gylfe E, Tengholm A (2010) cAMP mediators of pulsatile insulin secretion from glucose-stimulated single beta-cells. J Biol Chem 285:23007–23018PubMedCentralPubMedCrossRef

21.

Kim JW, Roberts CD, Berg SA, Caicedo A, Roper SD, Chaudhari N (2008) Imaging cyclic AMP changes in pancreatic islets of transgenic reporter mice. PLoS One 3:e2127PubMedCentralPubMedCrossRef

22.

Zhang J, Ma Y, Taylor SS, Tsien RY (2001) Genetically encoded reporters of protein kinase A activity reveal impact of substrate tethering. Proc Natl Acad Sci U S A 98:14997–15002PubMedCentralPubMedCrossRef

23.

Lou XL, Yu X, Chen XK et al (2003) Na+ channel inactivation: a comparative study between pancreatic islet beta-cells and adrenal chromaffin cells in rat. J Physiol 548:191–202PubMedCentralPubMedCrossRef

24.

Zhang C, Zhou Z (2002) Ca(2+)-independent but voltage-dependent secretion in mammalian dorsal root ganglion neurons. Nat Neurosci 5:425–430PubMed

25.

Dou HQ, Xu YF, Sun JP et al (2012) Thiopental-induced insulin secretion via activation of IP3-sensitive calcium stores in rat pancreatic beta-cells. Am J Physiol Cell Physiol 302:C796–C803PubMedCrossRef

26.

Rorsman P (1997) The pancreatic beta-cell as a fuel sensor: an electrophysiologist’s viewpoint. Diabetologia 40:487–495PubMedCrossRef

27.

Willoughby D, Cooper DM (2007) Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev 87:965–1010PubMedCrossRef

28.

Roger B, Papin J, Vacher P et al (2011) Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells. Diabetologia 54:390–402PubMedCrossRef

29.

Merrins MJ, Stuenkel EL (2008) Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic beta-cells. J Physiol 586:5367–5381PubMedCentralPubMedCrossRef

30.

Zhang X, Candas M, Griko NB, Taussig R, Bulla LA Jr (2006) A mechanism of cell death involving an adenylyl cyclase/PKA signaling pathway is induced by the Cry1Ab toxin of Bacillus thuringiensis. Proc Natl Acad Sci U S A 103:9897–9902PubMedCentralPubMedCrossRef

31.

Katz B (1969) The release of neural transmitter substances. Liverpool University Press, Liverpool

32.

Neher E, Sakaba T (2008) Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59:861–872PubMedCrossRef

33.

Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547PubMedCrossRef

34.

Ammala C, Ashcroft FM, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363:356–358PubMedCrossRef

35.

Gustavsson N, Lao Y, Maximov A et al (2008) Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice. Proc Natl Acad Sci U S A 105:3992–3997PubMedCentralPubMedCrossRef

36.

Michael DJ, Ritzel RA, Haataja L, Chow RH (2006) Pancreatic beta-cells secrete insulin in fast- and slow-release forms. Diabetes 55:600–607PubMedCrossRef

37.

von Ruden L, Neher E (1993) A Ca-dependent early step in the release of catecholamines from adrenal chromaffin cells. Science 262:1061–1065CrossRef

38.

Zhang B, Sun L, Yang YM et al (2011) Action potential bursts enhance transmitter release at a giant central synapse. J Physiol 589:2213–2227PubMedCentralPubMedCrossRef

39.

Everett KL, Cooper DM (2013) An improved targeted cAMP sensor to study the regulation of adenylyl cyclase 8 by Ca2+ entry through voltage-gated channels. PLoS One 8:e75942PubMedCentralPubMedCrossRef

40.

Tian G, Sandler S, Gylfe E, Tengholm A (2011) Glucose- and hormone-induced cAMP oscillations in alpha- and beta-cells within intact pancreatic islets. Diabetes 60:1535–1543PubMedCentralPubMedCrossRef

41.

Willoughby D, Masada N, Wachten S et al (2010) AKAP79/150 interacts with AC8 and regulates Ca2+-dependent cAMP synthesis in pancreatic and neuronal systems. J Biol Chem 285:20328–20342PubMedCentralPubMedCrossRef

42.

Leech CA, Castonguay MA, Habener JF (1999) Expression of adenylyl cyclase subtypes in pancreatic beta-cells. Biochem Biophys Res Commun 254:703–706PubMedCrossRef

43.

Fonseca SG, Urano F, Weir GC, Gromada J, Burcin M (2012) Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion. Nat Cell Biol 14:1105–1112PubMedCentralPubMedCrossRef

44.

Takahashi N, Kishimoto T, Nemoto T, Kadowaki T, Kasai H (2002) Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297:1349–1352PubMedCrossRef

Titel: Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells
verfasst von: Haiqiang Dou
Changhe Wang
Xi Wu
Lijun Yao
Xiaoyu Zhang
Sasa Teng
Huadong Xu
Bin Liu
Qihui Wu
Quanfeng Zhang
Meiqin Hu
Yeshi Wang
Li Wang
Yi Wu
Shujiang Shang
Xinjiang Kang
Lianghong Zheng
Jin Zhang
Matthieu Raoux
Jochen Lang
Qing Li
Jing Su
Xiao Yu
Liangyi Chen
Zhuan Zhou
Publikationsdatum: 01.02.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3437-z

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2015

Surrogate measures of insulin resistance: does one size fit all?

Mind the gap: connexins and cell–cell communication in the diabetic kidney

Single-centre study of 628 adult, primary kidney transplant recipients showing no unfavourable effect of new-onset diabetes after transplant

Surrogate measures of insulin sensitivity vs the hyperinsulinaemic–euglycaemic clamp: a meta-analysis. Are there not some surrogate indexes lost in this story? Reply to Bastard JP, Rabasa-Lhoret R, Laville M and Disse E [letter]

Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice