Serotonergic modulation of persistent sodium currents and membrane excitability via cyclic AMP-protein kinase A cascade in mesencephalic V neurons.
In rat mesencephalic trigeminal (Mes V) neurons, persistent sodium currents in conjunction with low-threshold potassium currents are critical for generation of subthreshold membrane oscillations and onset of burst behavior. Here we demonstrate that the cAMP/protein kinase A (PKA) signaling pathway modulates persistent sodium currents. In particular, we show that elevation of cAMP suppresses a low-threshold I(NaP) via a PKA intracellular pathway. Bath application of forskolin (20 microM), a stimulant for the production of cAMP, reduced the peak I(NaP). 1,9-Dideoxy-forskolin (20 microM), an inactive form of forskolin, produced minimal effects on I(NaP), and the membrane-permeable cAMP analogue 8-bromo-cAMP (500 microM) mimicked the effect of forskolin. Additionally, preapplication of H89 (2 microM), a specific PKA inhibitor, suppressed the effect of forskolin, suggesting the involvement of the cAMP/PKA intracellular signaling pathway in this modulation. 5-HT receptor stimulation (20 microM) also mimicked the modulation of I(NaP) by forskolin via the cAMP/PKA-dependent signaling pathway. Current clamp analysis demonstrated that voltage-dependent membrane resonance in response to a ZAP input current at depolarized holding potentials (approximately -50 mV) was specifically suppressed by forskolin or 5-HT. Moreover, drug application enhanced frequency adaptation in response to a 1-sec current pulse. These results indicate that modulation of persistent sodium currents by a cAMP/PKA pathway can significantly alter the membrane excitability and discharge characteristics of Mes V neurons.
Department of Physiological Science and Brain Research Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.
Susumu
S
Tanaka
Scott H
SH
Chandler
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D014278:Trigeminal Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D011985:Receptors, Serotonin; D015222:Sodium Channels; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012701:Serotonin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases