Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Pancreatic β-Cells
Open accessAbstract
Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels mediate the pacemaker current (Ih or If) observed in electrically rhythmic cardiac and neuronal cells. Here we describe a hyperpolarization-activated time-dependent cationic current, beta-Ih, in pancreatic beta-cells. Transcripts for HCN1-4 were detected by RT-PCR and quantitative PCR in rat islets and MIN6 mouse insulinoma cells. beta-Ih in rat beta-cells and MIN6 cells displayed biophysical and pharmacological properties similar to those of HCN currents in cardiac and neuronal cells. Stimulation of cAMP production with forskolin/3-isobutyl-1-methylxanthine (50 microM) or dibutyryl-cAMP (1 mM) caused a significant rightward shift in the midpoint activation potential of beta-Ih, whereas expression of either specific small interfering (si)RNA against HCN2 (siHCN2b) or a dominant-negative HCN channel (HCN1-AAA) caused a near-complete inhibition of time-dependent beta-Ih. However, expression of siHCN2b in MIN6 cells had no affect on glucose-stimulated insulin secretion under normal or cAMP-stimulated conditions. Blocking beta-Ih in intact rat islets also did not affect membrane potential behavior at basal glucose concentrations. Taken together, our experiments provide the first evidence for functional expression of HCN channels in the pancreatic beta-cell.
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The cAMP-induced shift means that a significant depolarizing current will exist at physiologically meaningful membrane potentials; for example, about 20% of the maximal HCN current will be activated at -60 mV.
“This shift means a significant depolarizing current will exist at physiologically meaningful membrane potentials: for example, ~20% of the maximal HCN current will be activated at -60 mV (168).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [168]
The cAMP Modulation section (page not provided) reports that raising cAMP shifted the activation midpoint in MIN6 cells from −88 to −74 mV. The Discussion (page not provided) reports inward currents activated by pulses as shallow as −60 mV, but the paper does not state that approximately 20% of maximal current is activated there or establish that this fraction exists at physiological membrane potentials. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe HCN current is blocked by ZD7288 and cilobradine, and these blockers do not affect glucose- and forskolin-induced insulin secretion.
“Pharmacologically, the HCN current is blocked by ZD7288 and cilobradine. These blockers do not affect glucose- and forskolin-induced insulin secretion (168).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [168]
The β-Ih inhibitor section reports that both ZD7288 and cilobradine block the HCN current. But the Effects of ZD7288 and Cilobradine on Insulin Secretion section reports that ZD7288 significantly reduced glucose-stimulated secretion, while cilobradine did not. The forskolin/IBMX secretion result concerns HCN2 knockdown, not either blocker; page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn the presence of cAMP, activation of HCN channels is shifted to more positive membrane potentials, with half-maximal activation at -74 mV in the presence of forskolin and IBMX.
“In the presence of cAMP, however, activation of HCN channels is shifted to more positive membrane potentials (half maximal at -74 mV in the presence of forskolin and IBMX).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [168]
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References 50 · Cited by 33
Research works printed but not linked: 1
- Furman B, Pyne N, Flatt P, O'Harte F 2004 Targeting -cell cyclic 3Ј5Ј adenosine monophosphate for the de- velopment of novel drugs for treating type 2 diabetes mellitus. A review. J Pharm Pharmacol 56:1477-1492
- Authors
- El-Kholy, W., MacDonald, P. E., Fox, J. M., Bhattacharjee, A., Xue, T., Gao, X., Zhang, Y., Stieber, J., Li, R. A., Tsushima, R. G., & Wheeler, M. B.
- Affiliations
- University of Toronto (CA)
- University of Alberta (CA)
- Johns Hopkins University (US)
- Departments of Medicine and Physiology (W.E.-K., J.M.F., A.B., X.G., Y.Z., R.G.T., M.B.W.), University of Toronto, Toronto, Ontario, Canada M5S 1A8;
- Technical University of Munich (DE)
- Corresponding author
- Tsushima, Robert G.
- Wheeler, Michael B.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-03-01
- Volume
- 21
- Issue
- 3
- Pages
- 753-764
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2038339611
- Cited by
- 33
- References
- 50
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 6 · 2013: 2 · 2012: 2
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- King's College London
- University of Toronto
- University of California, Davis
- Canadian Institutes of Health Research
- Banting and Best Diabetes Centre, University of Toronto
- National Heart, Lung, and Blood Institute (R01HL072857)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- HCN channels, pancreatic beta cells, pacemaker current, HCN2, cyclic AMP, glucose-stimulated insulin secretion, MIN6 cells, islets, siRNA knockdown, membrane potential
- MeSH terms
- Insulin Secretion, Cyclic AMP, Animals, Benzazepines, Cells, Cultured, Electrophysiology, Exocytosis, Insulin, Insulinoma, Membrane Potentials, Piperidines, Pyrimidines, Potassium Channels, Potassium Channel Blockers, RNA, Small Interfering, Insulin-Secreting Cells, Mice, Rats, Cyclic Nucleotide-Gated Cation Channels, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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