Abstract
BackgroundThe modulation of voltage-dependent Na+ channels by lipid metabolites such as arachidonic acid or eicosanoids plays a role in physiological functions as well as in degenerative diseases. So far TTX-resistant channels were found mainly to be regulated by lipid metabolites.ResultsWe investigated the lipid-dependent modulation of TTX-sensitive (TTX-s) Na+ channels using β-bungarotoxin (β-BuTX, 10 pM), which has an intrinsic phospholipase-A2 activity, and indomethacin (10 μM), which blocks cyclooxygenase activity in primary cerebellar neurons. To investigate TTX-s Na+ channels, whole-currents were measured under K+-free conditions and blocked by 10 nM TTX. The currents resulting from calculating the difference of currents measured in the presence and the absence of TTX were used for further analysis. Application of indomethacin mainly changed the current kinetics but has only minor effects on voltage-dependence. In contrast β-BuTX increased the maximal current amplitude and shifted the voltage-dependent activation towards more negative potentials. The effects of β-BuTX were blocked by indomethacin. Analysis of lipid metabolites which accumulate by treatment with β-BuTX using MALDI-TOF MS showed an increase of cyclooxygenase reaction products in relation to arachidonic acid.ConclusionsIn summary, we conclude that TTX-sensitive Na+ channels can be directly modulated by cyclooxygenase reaction products leading to higher activity at less depolarized potentials and subsequent higher excitability of neurons. Since activation of cyclooxygenase is also involved in pathways leading to apoptotic cells death this could play a role in degenerative diseases of the CNS and highlights a possible protective effect of cyclooxygenase inhibition.
Highlights
The modulation of voltage-dependent Na+ channels by lipid metabolites such as arachidonic acid or eicosanoids plays a role in physiological functions as well as in degenerative diseases
Under K+-free conditions, depolarization of cerebellar granule neurons (CGN) cells from a holding potential of -70 Membrane voltage (mV) led to the activation of fast activating and inactivating inward currents
These currents activated at potentials more positive than -40 mV which peaked at -10 mV
Summary
The modulation of voltage-dependent Na+ channels by lipid metabolites such as arachidonic acid or eicosanoids plays a role in physiological functions as well as in degenerative diseases. Na+ channels are known to be modulated by lipid metabolites, such as arachidonic acid or prostaglandins These modulations serve physiological functions such as neurotransmitter-dependent change in excitability, pain generation or inflammation-dependent hyperalgesia [1,2,3,4,5,6,7]. Direct application of arachidonic acid reduces Na+ channel activity by changing the maximal current amplitude, influencing Na+ current inactivation kinetics and shifting the voltage-dependent activation [5,10,11] These effects seem to be one of the major mechanisms of dopamine-induced decrease in neurotransmitter release and reduction of Na+-dependent action potentials [10]. The effects of arachidonic acid seem to be more mediated by the metabolites of arachidonic acid
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