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. 1997 Aug 15;503(Pt 1):87–97. doi: 10.1111/j.1469-7793.1997.087bi.x

Neurotensin inhibition of the hyperpolarization-activated cation current (Ih) in the rat substantia nigra pars compacta implicates the protein kinase C pathway.

L Cathala 1, D Paupardin-Tritsch 1
PMCID: PMC1159889  PMID: 9288677

Abstract

1. Whole-cell patch-clamp recording was performed from principal neurones of the substantia nigra pars compacta (SNc). In 66% of these neurones, neurotensin (NT) induced, at -60 mV, an inward current associated with an increase in conductance. 2. Principal neurones displayed, in response to hyperpolarizing voltage steps, the voltage-dependent inward cationic current, Ih. This current activated at potentials more negative than -65 mV and reached a maximum at -106 +/- 4 mV, with a half-activation potential of -86 +/- 3 mV. Its estimated reversal potential was -43 +/- 7 mV and its activation curve was fitted with two exponentials. 3. In 41% of neurones showing the inward current, NT (0.5 microM) also reversibly reduced the amplitude of Ih. The diminution was 48.5 +/- 12% when voltage steps were made from -60 to -95 mV. The decrease in Ih resulted from a reduction in the maximal current with no change in the voltage dependence of activation. 4. Forskolin (10 microM), an activator of adenylate cyclase, increased Ih by shifting its activation range to more positive potentials, but it did not alter the NT inhibition of Ih. 5. The effect of NT was blocked by staurosporine (0.5 microM) and by PKC-(19-31) (0.5 microM), a specific protein kinase C (PKC) inhibitor, but was unaffected by Walsh's peptide (100 microM), a specific inhibitor of protein kinase A. The reduction of Ih was mimicked by 1-oleoyl-2-acetyl-sn-glycerol (0.5-10 microM), an analogue of diacylglycerol, an endogenous PKC activator. 6. These results suggest that the inhibition of Ih by NT involves a phosphorylation mechanism that implies activation of PKC.

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Selected References

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  1. Banks M. I., Pearce R. A., Smith P. H. Hyperpolarization-activated cation current (Ih) in neurons of the medial nucleus of the trapezoid body: voltage-clamp analysis and enhancement by norepinephrine and cAMP suggest a modulatory mechanism in the auditory brain stem. J Neurophysiol. 1993 Oct;70(4):1420–1432. doi: 10.1152/jn.1993.70.4.1420. [DOI] [PubMed] [Google Scholar]
  2. Bobker D. H., Williams J. T. Serotonin augments the cationic current Ih in central neurons. Neuron. 1989 Jun;2(6):1535–1540. doi: 10.1016/0896-6273(89)90041-x. [DOI] [PubMed] [Google Scholar]
  3. Boudin H., Pélaprat D., Rostène W., Beaudet A. Cellular distribution of neurotensin receptors in rat brain: immunohistochemical study using an antipeptide antibody against the cloned high affinity receptor. J Comp Neurol. 1996 Sep 9;373(1):76–89. doi: 10.1002/(SICI)1096-9861(19960909)373:1<76::AID-CNE7>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  4. Brown H., Difrancesco D. Voltage-clamp investigations of membrane currents underlying pace-maker activity in rabbit sino-atrial node. J Physiol. 1980 Nov;308:331–351. doi: 10.1113/jphysiol.1980.sp013474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Budde T., White J. A., Kay A. R. Hyperpolarization-activated Na(+)-K+ current (Ih) in neocortical neurons is blocked by external proteolysis and internal TEA. J Neurophysiol. 1994 Dec;72(6):2737–2742. doi: 10.1152/jn.1994.72.6.2737. [DOI] [PubMed] [Google Scholar]
  6. Chien P. Y., Farkas R. H., Nakajima S., Nakajima Y. Single-channel properties of the nonselective cation conductance induced by neurotensin in dopaminergic neurons. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14917–14921. doi: 10.1073/pnas.93.25.14917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol. 1993;55:455–472. doi: 10.1146/annurev.ph.55.030193.002323. [DOI] [PubMed] [Google Scholar]
  8. DiFrancesco D., Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature. 1991 May 9;351(6322):145–147. doi: 10.1038/351145a0. [DOI] [PubMed] [Google Scholar]
  9. Farkas R. H., Chien P. Y., Nakajima S., Nakajima Y. Properties of a slow nonselective cation conductance modulated by neurotensin and other neurotransmitters in midbrain dopaminergic neurons. J Neurophysiol. 1996 Sep;76(3):1968–1981. doi: 10.1152/jn.1996.76.3.1968. [DOI] [PubMed] [Google Scholar]
  10. Farkas R. H., Nakajima S., Nakajima Y. Neurotensin excites basal forebrain cholinergic neurons: ionic and signal-transduction mechanisms. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2853–2857. doi: 10.1073/pnas.91.7.2853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hainsworth A. H., Röper J., Kapoor R., Ashcroft F. M. Identification and electrophysiology of isolated pars compacta neurons from guinea-pig substantia nigra. Neuroscience. 1991;43(1):81–93. doi: 10.1016/0306-4522(91)90419-o. [DOI] [PubMed] [Google Scholar]
  12. Harris N. C., Constanti A. Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro. J Neurophysiol. 1995 Dec;74(6):2366–2378. doi: 10.1152/jn.1995.74.6.2366. [DOI] [PubMed] [Google Scholar]
  13. Hermans E., Maloteaux J. M., Octave J. N. Phospholipase C activation by neurotensin and neuromedin N in Chinese hamster ovary cells expressing the rat neurotensin receptor. Brain Res Mol Brain Res. 1992 Oct;15(3-4):332–338. doi: 10.1016/0169-328x(92)90126-v. [DOI] [PubMed] [Google Scholar]
  14. House C., Kemp B. E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain. Science. 1987 Dec 18;238(4834):1726–1728. doi: 10.1126/science.3686012. [DOI] [PubMed] [Google Scholar]
  15. Jiang Z. G., Pessia M., North R. A. Dopamine and baclofen inhibit the hyperpolarization-activated cation current in rat ventral tegmental neurones. J Physiol. 1993 Mar;462:753–764. doi: 10.1113/jphysiol.1993.sp019580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jiang Z. G., Pessia M., North R. A. Neurotensin excitation of rat ventral tegmental neurones. J Physiol. 1994 Jan 1;474(1):119–129. doi: 10.1113/jphysiol.1994.sp020007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lacey M. G., Mercuri N. B., North R. A. Two cell types in rat substantia nigra zona compacta distinguished by membrane properties and the actions of dopamine and opioids. J Neurosci. 1989 Apr;9(4):1233–1241. doi: 10.1523/JNEUROSCI.09-04-01233.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mayer M. L., Westbrook G. L. A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones. J Physiol. 1983 Jul;340:19–45. doi: 10.1113/jphysiol.1983.sp014747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mercuri N. B., Bonci A., Calabresi P., Stefani A., Bernardi G. Properties of the hyperpolarization-activated cation current Ih in rat midbrain dopaminergic neurons. Eur J Neurosci. 1995 Mar 1;7(3):462–469. doi: 10.1111/j.1460-9568.1995.tb00342.x. [DOI] [PubMed] [Google Scholar]
  20. Mercuri N. B., Stratta F., Calabresi P., Bernardi G. Neurotensin induces an inward current in rat mesencephalic dopaminergic neurons. Neurosci Lett. 1993 Apr 30;153(2):192–196. doi: 10.1016/0304-3940(93)90320-k. [DOI] [PubMed] [Google Scholar]
  21. Palacios J. M., Kuhar M. J. Neurotensin receptors are located on dopamine-containing neurones in rat midbrain. Nature. 1981 Dec 10;294(5841):587–589. doi: 10.1038/294587a0. [DOI] [PubMed] [Google Scholar]
  22. Pape H. C., McCormick D. A. Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature. 1989 Aug 31;340(6236):715–718. doi: 10.1038/340715a0. [DOI] [PubMed] [Google Scholar]
  23. Pape H. C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol. 1996;58:299–327. doi: 10.1146/annurev.ph.58.030196.001503. [DOI] [PubMed] [Google Scholar]
  24. Pedarzani P., Storm J. F. Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11716–11720. doi: 10.1073/pnas.92.25.11716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pinnock R. D. Neurotensin depolarizes substantia nigra dopamine neurones. Brain Res. 1985 Jul 8;338(1):151–154. doi: 10.1016/0006-8993(85)90258-6. [DOI] [PubMed] [Google Scholar]
  26. Rüegg U. T., Burgess G. M. Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharmacol Sci. 1989 Jun;10(6):218–220. doi: 10.1016/0165-6147(89)90263-0. [DOI] [PubMed] [Google Scholar]
  27. Snider R. M., Forray C., Pfenning M., Richelson E. Neurotensin stimulates inositol phospholipid metabolism and calcium mobilization in murine neuroblastoma clone N1E-115. J Neurochem. 1986 Oct;47(4):1214–1218. doi: 10.1111/j.1471-4159.1986.tb00742.x. [DOI] [PubMed] [Google Scholar]
  28. Solomon J. S., Nerbonne J. M. Two kinetically distinct components of hyperpolarization-activated current in rat superior colliculus-projecting neurons. J Physiol. 1993 Sep;469:291–313. doi: 10.1113/jphysiol.1993.sp019815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tokimasa T., Akasu T. Cyclic AMP regulates an inward rectifying sodium-potassium current in dissociated bull-frog sympathetic neurones. J Physiol. 1990 Jan;420:409–429. doi: 10.1113/jphysiol.1990.sp017920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Watts A. E., Williams J. T., Henderson G. Baclofen inhibition of the hyperpolarization-activated cation current, Ih, in rat substantia nigra zona compacta neurons may be secondary to potassium current activation. J Neurophysiol. 1996 Oct;76(4):2262–2270. doi: 10.1152/jn.1996.76.4.2262. [DOI] [PubMed] [Google Scholar]
  31. Wu T., Wang H. L. Protein kinase C mediates neurotensin inhibition of inwardly rectifying potassium currents in rat substantia nigra dopaminergic neurons. Neurosci Lett. 1995 Jan 23;184(2):121–124. doi: 10.1016/0304-3940(94)11185-l. [DOI] [PubMed] [Google Scholar]
  32. Yanagihara K., Noma A., Irisawa H. Reconstruction of sino-atrial node pacemaker potential based on the voltage clamp experiments. Jpn J Physiol. 1980;30(6):841–857. doi: 10.2170/jjphysiol.30.841. [DOI] [PubMed] [Google Scholar]
  33. Yung W. H., Häusser M. A., Jack J. J. Electrophysiology of dopaminergic and non-dopaminergic neurones of the guinea-pig substantia nigra pars compacta in vitro. J Physiol. 1991 May;436:643–667. doi: 10.1113/jphysiol.1991.sp018571. [DOI] [PMC free article] [PubMed] [Google Scholar]

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