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The Journal of Neuroscience, March 14, 2007, 27(11):2802-2814; doi:10.1523/JNEUROSCI.4376-06.2007

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Cellular/Molecular
HCN Pacemaker Channel Activation Is Controlled by Acidic Lipids Downstream of Diacylglycerol Kinase and Phospholipase A2

Keri J. Fogle,¹ Alex K. Lyashchenko,² Harma K. Turbendian,² and Gareth R. Tibbs^2,3

¹Center for Neurobiology and Behavior and the Departments of ²Anesthesiology and ³Pharmacology, Columbia University, New York, New York 10032

Correspondence should be addressed to Gareth R. Tibbs, Department of Anesthesiology, Eye Institute Research Annex, EI3-305, 160 Fort Washington Avenue, New York, NY 10032. Email: grt1{at}columbia.edu

Hyperpolarization-activated pacemaker currents (I_H) contribute to the subthreshold properties of excitable cells and thereby influence behaviors such as synaptic integration and the appearance and frequency of intrinsic rhythmic activity. Accordingly, modulation of I_H contributes to cellular plasticity. Although I_H activation is regulated by a plethora of neurotransmitters, including some that act via phospholipase C (PLC), the only second messengers known to alter I_H voltage dependence are cAMP, internal protons (H⁺_Is), and phosphatidylinositol-4,5-phosphate. Here, we show that 4ß-phorbol-12-myristate-13-acetate (4ßPMA), a stereoselective C-1 diacylglycerol-binding site agonist, enhances voltage-dependent opening of wild-type and cAMP/H⁺_I-uncoupled hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channels, but does not alter gating of the plant hyperpolarization-activated channel, KAT1. Pharmacological analysis indicates that 4ßPMA exerts its effects on HCN gating via sequential activation of PKC and diacylglycerol kinase (DGK) coupled with upregulation of MAPK (mitogen-activated protein kinase) and phospholipase A2 (PLA2), but its action is independent of phosphoinositide kinase 3 (PI3K) and PI4K. Demonstration that both phosphatidic acid and arachidonic acid (AA) directly facilitate HCN gating suggests that these metabolites may serve as the messengers downstream of DGK and PLA2, respectively. 4ßPMA-mediated suppression of the maximal HCN current likely arises from channel interaction with AA coupled with an enhanced membrane retrieval triggered by the same pathways that modulate channel gating. These results indicate that regulation of excitable cell behavior by neurotransmitter-mediated modulation of I_H may be exerted via changes in three signaling lipids in addition to the allosteric actions of cAMP and H⁺_Is.

Key words: phosphatidic acid; arachidonic acid; protein kinase C; diacylglycerol kinase; phospholipase A2; mitogen-activated protein kinase

---

Received Oct. 6, 2006; revised Jan. 31, 2006; accepted Feb. 1, 2007.

Correspondence should be addressed to Gareth R. Tibbs, Department of Anesthesiology, Eye Institute Research Annex, EI3-305, 160 Fort Washington Avenue, New York, NY 10032. Email: grt1{at}columbia.edu

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