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Lund, Per-Eric
Publications (7 of 7) Show all publications
Gandasi, N. R., Yin, P., Riz, M., Chibalina, M. V., Cortese, G., Lund, P.-E., . . . Barg, S. (2017). Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes. Journal of Clinical Investigation, 127(6), 2353-2364
Open this publication in new window or tab >>Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes
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2017 (English)In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 127, no 6, p. 2353-2364Article in journal (Refereed) Published
Abstract [en]

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in β cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II-III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

National Category
Cell and Molecular Biology
Research subject
Molecular Cellbiology
Identifiers
urn:nbn:se:uu:diva-321935 (URN)10.1172/JCI88491 (DOI)000402620800029 ()28481223 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationThe Swedish Brain FoundationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2018-03-11Bibliographically approved
Marshall, M., Lund, P.-E. & Barg, S. (2017). Molecular Mechanisms of V-SNARE Function in Secretory Granule Exocytosis. Paper presented at 58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA. Biophysical Journal, 112(3), 395A-395A
Open this publication in new window or tab >>Molecular Mechanisms of V-SNARE Function in Secretory Granule Exocytosis
2017 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 395A-395AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Biophysics
Identifiers
urn:nbn:se:uu:diva-332760 (URN)000402375600962 ()
Conference
58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA
Available from: 2017-11-06 Created: 2017-11-06 Last updated: 2017-11-06
Macsari, I., Besidski, Y., Csjernyik, G., Nilsson, L. I., Sandberg, L., Yngve, U., . . . Arvidsson, P. I. (2012). 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models. Journal of Medicinal Chemistry, 55(15), 6866-6880
Open this publication in new window or tab >>3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
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2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 15, p. 6866-6880Article in journal (Refereed) Published
Abstract [en]

The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-179901 (URN)10.1021/jm300623u (DOI)000307264100019 ()
Available from: 2012-08-28 Created: 2012-08-27 Last updated: 2017-12-07
Macsari, I., Sandberg, L., Besidski, Y., Gravenfors, Y., Ginman, T., Bylund, J., . . . Arvidsson, P. I. (2011). Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship. Bioorganic & Medicinal Chemistry Letters, 21(13), 3871-3876
Open this publication in new window or tab >>Phenyl isoxazole voltage-gated sodium channel blockers: structure and activity relationship
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2011 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, no 13, p. 3871-3876Article in journal (Refereed) Published
Abstract [en]

Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na(V)1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure-activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.

Keywords
Sodium channel blockers, Na(V)1.7 blocker, Neuropathic pain, Phenyl isoxazoles, Voltage-gated channel
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-155602 (URN)10.1016/j.bmcl.2011.05.041 (DOI)000291474300004 ()
Available from: 2011-06-27 Created: 2011-06-27 Last updated: 2018-01-12Bibliographically approved
Gustafsson, A. J., Ingelman-Sundberg, H., Dzabic, M., Awasum, J., Nguyen, K. H., Östenson, C.-G., . . . Islam, M. S. (2005). Ryanodine receptor-operated activation of TRP-like channels can trigger critical Ca2+ signaling events in pancreatic beta-cells. The FASEB Journal, 19(2), 301-303
Open this publication in new window or tab >>Ryanodine receptor-operated activation of TRP-like channels can trigger critical Ca2+ signaling events in pancreatic beta-cells
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2005 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 19, no 2, p. 301-303Article in journal (Refereed) Published
Abstract [en]

There is little information available concerning the link between the ryanodine (RY) receptors and the downstream Ca(2+) signaling events in beta-cells. In fura-2 loaded INS-1E cells, activation of RY receptors by 9-methyl 5,7-dibromoeudistomin D (MBED) caused a rapid rise of [Ca(2+)]i followed by a plateau and repetitive [Ca(2+)]i spikes on the plateau. The [Ca(2+)]i plateau was abolished by omission of extracellular Ca(2+) and by SKF 96365. In the presence of SKF 96365, MBED produced a transient increase of [Ca(2+)]i, which was abolished by thapsigargin. Activation of RY receptors caused Ca(2+) entry even when the ER Ca(2+) pool was depleted by thapsigargin. The [Ca(2+)]i plateau was not inhibited by nimodipine or ruthenium red, but was inhibited by membrane depolarization, La(3+), Gd(3+), niflumic acid, and 2-aminoethoxydiphenyl borate, agents that inhibit the transient receptor potential channels. The [Ca(2+)]i spikes were inhibited by nimodipine and ryanodine, indicating that they were due to Ca(2+) influx through the voltage-gated Ca(2+) channels and Ca(2+)-induced Ca(2+) release (CICR). Activation of RY receptors depolarized membrane potential as measured by patch clamp. Thus, activation of RY receptors leads to coherent changes in Ca(2+) signaling, which includes activation of TRP-like channels, membrane depolarization, activation of the voltage-gated Ca(2+) channels and CICR.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-132280 (URN)10.1096/fj.04-2621fje (DOI)15572434 (PubMedID)
Available from: 2010-10-18 Created: 2010-10-18 Last updated: 2017-12-12Bibliographically approved
Lund, P.-E., Shariatmadari, R., Uustare, A., Detheux, M., Parmentier, M., Kukkonen, J. & Akerman, K.-E. (2000). The orexin OX(1) receptor activates a novel Ca2+ influx pathway necessary for coupling to phospholipase C*. J Biol Chem, 275, 30806
Open this publication in new window or tab >>The orexin OX(1) receptor activates a novel Ca2+ influx pathway necessary for coupling to phospholipase C*
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2000 (English)In: J Biol Chem, Vol. 275, p. 30806-Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-57751 (URN)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2015-08-12
Akerman, K. E. O., Nasman, J., Lund, P.-E., Shariatmadari, R. & Kukkonen, J. P. (1998). Endogenous extracellular purine nucleotides redirect alpha2-adrenoceptor signaling. FEBS Lett., 430, 209
Open this publication in new window or tab >>Endogenous extracellular purine nucleotides redirect alpha2-adrenoceptor signaling
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1998 (English)In: FEBS Lett., Vol. 430, p. 209-Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-57915 (URN)
Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2015-08-12
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