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March 14, 2007Journal of NeuroscienceOpen Access

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

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Key result

The diacylglycerol-mimetic 4βPMA enhances voltage-dependent opening of HCN pacemaker channels via sequential activation of PKC and diacylglycerol kinase coupled with upregulation of MAPK and phospholipase A2.

Population

Xenopus oocytes expressing wild-type and mutant hyperpolarization-activated, cyclic nucleotide-regulated…

Comparison

4beta-phorbol-12-myristate-13-acetate and other… vs Vehicle control or inactive stereoisomer 4alphaPMA

Design

Preclinical

Authors

KFKeri J. FogleUniversity of PittsburghALAlex K. LyashchenkoColumbia University Irving Medical CenterHTHarma K. TurbendianIllinois College

Discussion

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Implication

Identifies novel I(H) modulation by phospholipids; leaves open roles in neuronal and cardiac pacemaking.

Structured PICO

P
Population
Xenopus oocytes expressing wild-type and mutant hyperpolarization-activated, cyclic nucleotide-regulated (HCN1, HCN2) channels and KAT1 channels
I
Intervention
4beta-phorbol-12-myristate-13-acetate (4betaPMA) and other pharmacological agents (phosphatidic acid, arachidonic acid)
C
Comparator
Vehicle control (DMSO, ethanol, or H2O) or inactive stereoisomer 4alphaPMA
O
Outcome
Voltage-dependent opening (V1/2 of activation) and maximal current amplitude of HCN channelssurrogate

HCN pacemaker channel activation is modulated by acidic lipids (phosphatidic acid and arachidonic acid) downstream of diacylglycerol kinase and phospholipase A2, revealing a novel lipid signaling pathway for I(H) regulation.

Limitations

  • In vitro study using heterologous expression in Xenopus oocytes, which may not fully replicate native mammalian cell physiology.

Cite This Study

Fogle et al. (2007) studied this question. 4β-phorbol-12-myristate-13-acetate (4βPMA) vs. Vehicle (DMSO) or 4αPMA was evaluated on Voltage-dependent opening of HCN channels (shift in V1/2). The diacylglycerol-mimetic 4βPMA enhances voltage-dependent opening of HCN pacemaker channels via sequential activation of PKC and diacylglycerol kinase coupled with upregulation of MAPK and phospholipase A2.

synapsesocial.com/papers/6a651000ef7343fdf0cd36c0https://doi.org/10.1523/jneurosci.4376-06.2007
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Also Consider

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