Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons

Zhengyu Cao, Yanjun Cui, Eric Busse, Suneet Mehrotra, Jon D. Rainier, Thomas F. Murray

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca2+ oscillations, and an inhibition of Kv channel function with similar potencies. In addition, an array of selective as well as universal Kv channel inhibitors mimicked gambierol in augmenting spontaneous Ca2+ oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of Kv channels underlying the observed increase in spontaneous Ca2+ oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic [N-methyl-D-aspartate (NMDA)] and type I metabotropic glutamate receptors (mGluRs) inasmuch as MK-801 [NMDA receptor inhibitor; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate], S-(4)-CGP [S-(4)-carboxyphenylglycine], and MTEP [type I mGluR inhibitors; 3-((2-methyl-4-thiazolyl)ethynyl) pyridine] attenuated the response. In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra- 1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca2+ signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of K v channels.

Original languageEnglish
Pages (from-to)615-623
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume350
Issue number3
DOIs
StatePublished - 2014

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Voltage-Gated Potassium Channels
Neurons
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Dinoflagellida
Voltage-Gated Sodium Channel Agonists
Voltage-Gated Sodium Channel Blockers
Ciguatoxins
gambierol
Marine Toxins
Inositol 1,4,5-Trisphosphate Receptors
4-Aminopyridine
Metabotropic Glutamate Receptors
Imines
Dizocilpine Maleate
Potassium Channels
Type C Phospholipases
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Ether

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Molecular Medicine

Cite this

Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons. / Cao, Zhengyu; Cui, Yanjun; Busse, Eric; Mehrotra, Suneet; Rainier, Jon D.; Murray, Thomas F.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 350, No. 3, 2014, p. 615-623.

Research output: Contribution to journalArticle

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AU - Murray, Thomas F.

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