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Modulation of a voltage-activated potassium channel by peptide growth factor receptors
1Program of Excellence in Molecular Biology, University of California at San Francisco 94143.
Abstract:
Regulation of the activity of a cloned component of a voltage-activated K+ channel, Kv1.5, was studied by expressing the K+ channel and receptors for platelet-derived growth factor (PDGF) or fibroblast growth factor (FGF) simultaneously in Xenopus oocytes. Receptor activation mediated a decline in the Kv1.5 current amplitude, with a half-time of about 20 min. The reduction in K+ current amplitude occurred with little change in the kinetics or voltage sensitivity of activation. A similar phenomenon was found when the human thrombin or rat 5-HT1c receptors, two receptors that increase phospholipase C activity, were tested in coexpression experiments. A mutant FGF receptor, which does not activate phospholipase C-gamma 1 but retains several of its other functions, did not modulate the Kv1.5 current. Simultaneous injection of inositol trisphosphate and superfusion of phorbol 12-myristate 13-acetate reproduced the modulation of the Kv1.5 current. These results demonstrate that the PDGF and FGF receptors can modulate a voltage-activated K+ channel by increasing phospholipase C activity, and suggest that PDGF or FGF may be able to alter rapidly the electrical excitability of neurons.
Insights
Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors can regulate voltage-activated potassium (K+) channels. This modulation occurs via increased phospholipase C activity, potentially altering neuronal electrical excitability.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Physiology
Background:
- Voltage-activated potassium channels are crucial for neuronal electrical excitability.
- Growth factor receptors like PDGF and FGF play roles in cellular signaling.
- Understanding cross-talk between growth factor signaling and ion channel function is important.
Purpose of the Study:
- To investigate how platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor activation influences the activity of the Kv1.5 potassium channel.
- To elucidate the signaling pathway involved in this modulation.
Main Methods:
- Coexpression of Kv1.5 potassium channel and PDGF or FGF receptors in Xenopus oocytes.
- Electrophysiological recordings to measure Kv1.5 current amplitude and kinetics.
- Utilizing mutant receptors and specific signaling molecules (inositol trisphosphate, phorbol 12-myristate 13-acetate) to dissect the pathway.
Main Results:
- Activation of PDGF and FGF receptors led to a decrease in Kv1.5 current amplitude.
- The reduction in current occurred without significant changes in channel kinetics or voltage sensitivity.
- Receptors that increase phospholipase C activity (thrombin, 5-HT1c) mimicked this effect.
- A mutant FGF receptor unable to activate phospholipase C-gamma 1 did not modulate Kv1.5 current.
Conclusions:
- PDGF and FGF receptors modulate voltage-activated Kv1.5 channels through phospholipase C activation.
- This signaling pathway suggests that PDGF and FGF can rapidly influence neuronal electrical excitability.