PGE2 modulates the tetrodotoxin‐resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP‐protein kinase A cascade.
S England, S Bevan, RJ Docherty - The Journal of physiology, 1996 - Wiley Online Library
S England, S Bevan, RJ Docherty
The Journal of physiology, 1996•Wiley Online Library1. In current‐clamp recordings, 1 microM prostaglandin E2 (PGE2) increased the excitability
of neonatal rat dorsal root ganglion neurones. The current threshold for firing was reduced,
and the response to a constant suprathreshold stimulation was modified such that a single
evoked action potential was converted to a train of action potentials. The excitatory action of
PGE2 was still apparent when action potentials were evoked in the presence of 500 nM
tetrodotoxin. 2. In voltage‐clamp experiments 1 microM PGE2 frequently increased the …
of neonatal rat dorsal root ganglion neurones. The current threshold for firing was reduced,
and the response to a constant suprathreshold stimulation was modified such that a single
evoked action potential was converted to a train of action potentials. The excitatory action of
PGE2 was still apparent when action potentials were evoked in the presence of 500 nM
tetrodotoxin. 2. In voltage‐clamp experiments 1 microM PGE2 frequently increased the …
1. In current‐clamp recordings, 1 microM prostaglandin E2 (PGE2) increased the excitability of neonatal rat dorsal root ganglion neurones. The current threshold for firing was reduced, and the response to a constant suprathreshold stimulation was modified such that a single evoked action potential was converted to a train of action potentials. The excitatory action of PGE2 was still apparent when action potentials were evoked in the presence of 500 nM tetrodotoxin. 2. In voltage‐clamp experiments 1 microM PGE2 frequently increased the magnitude of the peak currents recorded, and caused a hyperpolarizing shift (of approximately 6 mV) in the activation curve for the tetrodotoxin‐resistant sodium current (TTX‐R INa). In some cells, the hyperpolarizing shift in the activation curve was accompanied by a decrease in peak conductance. PGE2 also caused a hyperpolarizing shift in the steady‐state inactivation curve for the sodium current. 3. Extracellular application of the cAMP analogue dibutyryl cAMP (dbcAMP) at a concentration of 1 mM produced effects on both the current‐voltage relationship and the steady‐state inactivation curve for the TTX‐R INa which were indistinguishable from those observed with PGE2. Prior exposure of the neurones to dbcAMP occluded the effect of a subsequent treatment with PGE2. 4. Forskolin (10 microM), a direct activator of adenylate cyclase, mimicked the effects of PGE2 and dbcAMP on TTX‐R INa. The inactive congener of forskolin, 1, 9‐dideoxyforskolin (10 microM), reduced the amplitude of TTX‐R INa, but did not evoke a hyperpolarizing shift in the activation curve. 5. Intracellular perfusion of the neurones with an inhibitor of protein kinase A inhibited the effect of PGE2 on TTX‐R INa. 6. PGE2 also reduced the amplitude of voltage‐gated potassium currents (IK), which will contribute to the excitatory action. The mechanisms underlying the changes in IK have yet to be elucidated. 7. We propose that the PGE2‐mediated increase in excitability in sensory neurones may be due, at least in part, to the cAMP‐protein kinase A‐dependent modulation of the tetrodotoxin‐resistant sodium channel.
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