Advertisement
Research Article| Volume 50, ISSUE 5, P337-344, September 01, 2001

Download started.

Ok

Long-term treatment with s-adenosylmethionine induces changes in presynaptic cam kinase II and synapsin I

      Abstract

      Background: According to current hypotheses, antidepressant drug action is the result of adaptive changes in neuronal signaling mechanisms rather than a primary effect on neurotransmitter transporters, receptors, or metabolic enzymes. Among the signaling mechanisms involved, protein kinases and phosphorylation have been shown to be modified by drug treatment. Presynaptic signaling (calcium/calmodulin-dependent protein kinase II [CaMKII]) and the protein machinery regulating transmitter release have been implicated in the action of these drugs.
      Methods: We investigated the effect of S-adenosylmethionine (SAM), a compound with putative antidepressant activity, on presynaptic CaMKII and its synaptic vesicle substrate synapsin I. The activity of CaMKII was assayed in synaptic subcellular fractions prepared from hippocampus (HI), frontal cortex (FCX), striatum (STR), and parieto-temporal cortex.
      Results: The kinase activity was increased after SAM treatment in the synaptic vesicle fraction of HI (31.7%), FCX (35.9%), and STR (18.4%). The protein level of CaMKII was also increased in synaptic vesicles of HI (40.4%). The synapsin I level was unchanged in synaptic vesicles but markedly increased in synaptic cytosol of HI (75.8%) and FCX (163.0%). No changes for both CaMKII and synapsin I level were found in homogenates, suggesting that synaptic protein changes are not explained by an increase in total level of proteins, but rather by translocation to nerve terminals.
      Conclusions: Similar to typical antidepressant drugs, SAM induces changes in CaMKII activity and increases synapsin I level in HI and FCX nerve terminals, suggesting a modulatory action on transmitter release.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Agnoli A.
        • Ruggieri S.
        • Cerone C.G.
        • et al.
        The dopamine hypothesis of depression.
        in: Grattini S. Schatauer F.K. Depressive Disorders. Verlag, Stuttgart1977: 447-458
        • Algeri S.
        • Catto E.
        • Curcio M.
        • Ponzio F.
        • Stramentinoli G.
        Changes in rat brain noradrenaline and serotonin after administration of S-adenosylmethionine.
        in: Zappia V. Usdin E. Salvatore S. Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System. Pergamon Press, New York1979: 81-87
        • Artigas F.
        • Romero L.
        • de Montigny C.
        • Blier P.
        Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists.
        Trends Neurosci. 1996; 19: 78-383
        • Benelli A.
        • Filaferro M.
        • Bertolini A.
        • Genedani S.
        Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats.
        Br J Pharmacol. 1999; 127: 645-654
        • Blier P.
        • de Montigny C.
        Current advances and trends in the treatment of depression.
        Trends Pharm Sci. 1994; 15: 220-225
        • Bottiglieri T.
        Ademetionine (S-adenosylmethionine) neuropharmacology.
        Exp Opin Invest Drugs. 1997; 6: 1-10
        • Bottiglieri T.
        • Godfrey P.
        • Flynn T.
        • Carney M.P.W.
        • Toone B.K.
        • Reynolds E.H.
        Cerebrospinal fluid S-adenosylmethionine ion in depression and dementia.
        J Neurol Neurosurg Psychiatry. 1990; 53: 1096-1098
        • Bressa G.M.
        S-adenosyl-L-methionine (SAMe) as antidepressant.
        Acta Neurol Scand. 1994; 89: 7-14
        • Castagna A.
        • Le Grazie C.
        • Accordini A.
        • Giulidori P.
        • Cavalli G.
        • Bottiglieri T.
        • et al.
        Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection.
        Neurology. 1995; 45: 1678-1683
        • Cochet C.
        • Chambaz E.M.
        Polyamine-mediated protein phosphorylations.
        Mol Cell Endocrinol. 1983; 30: 247-266
        • Consogno E.
        • Racagni G.
        • Popoli M.
        Modifications in brain CaM kinase II after long-term treatment with desmethylimipramine.
        Neuropsychopharmacology. 2001; 24: 21-30
        • Duman R.S.
        Novel therapeutic approaches beyond the serotonin receptor.
        Biol Psychiatry. 1998; 44: 324-335
        • Fava M.
        • Rosenbaum J.F.
        • MacLaughlin R.
        • Falk W.E.
        • Pollack M.H.
        • Cohen L.S.
        • Jones L.
        • Pill L.
        Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative antidepressant.
        J Psychiat Res. 1990; 24: 177-184
        • Glowinski J.
        • Iversen L.L.
        Regional studies of cathecolamines in the rat brain. I. The disposition of 3H-nor-epinephrine, 3H-dopamine and 3H-dopa in various regions of the brain.
        J Neurochem. 1966; 13: 655-669
        • Graves J.D.
        • Krebs E.G.
        Protein phosphorylation and signal transduction.
        Pharmacol Ther. 1999; 82: 111-121
        • Greengard P.
        • Valtorta F.
        • Czernik A.J.
        • Benfenati F.
        Synaptic vesicle phosphoproteins and regulation of synaptic function.
        Science. 1993; 259: 780-785
        • Hanson P.I.
        • Schulman H.
        Neuronal Ca2+/calmodulin-dependent protein kinases.
        Annu Rev Biochem. 1992; 61: 559-601
        • Huttner W.B.
        • Schiebler W.
        • Greengard P.
        • De Camilli P.
        Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation.
        J Cell Biol. 1983; 96: 1373-1388
        • Hyman S.E.
        • Nestler E.J.
        Initiation and adaptation.
        Am J Psychiatry. 1996; 153: 151-162
        • Mongeau R.
        • Blier P.
        • de Montigny C.
        The serotonergic and noradrenergic systems of the hippocampus.
        Brain Res Rev. 1997; 23: 145-195
        • Mudd S.H.
        • Cantoni G.L.
        Biological transmethylation methyl group neogenesis and other “one carbon metabolic reaction dependent upon tetrahydrofolic acid.”.
        in: Florkin M. Stotz E.H. Comprehensive Biochemistry. Vol. 15. Elsevier, New York1964: 1-47
        • Ocorr K.A.
        • Schulman H.
        Activation of multifunctional Ca2+/calmodulin-dependent kinase in intact hippocampal slices.
        Neuron. 1991; 6: 907-914
        • Pilc A.
        • Branski P.
        • Palucha A.
        • Aronowski J.
        The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain.
        Neuropharmacology. 1999; 38: 597-603
        • Popoli M.
        • Brunello N.
        • Perez J.
        • Racagni G.
        Second messenger regulated protein kinases in the brain.
        J Neurochem. 2000; 74: 21-33
        • Popoli M.
        • Vocaturo C.
        • Perez J.
        • Smeraldi E.
        • Racagni G.
        Presynaptic Ca2+/calmodulin-dependent protein kinase II.
        Mol Pharmacol. 1995; 48: 623-629
        • Popoli M.
        • Zanotti S.
        • Radaelli R.
        • Gaggianesi C.
        • Verona M.
        • Brunello N.
        • et al.
        The neurotransmitter release machinery as a site of action for psychotropic drugs.
        Soc Neurosci Abs. 1997; 23: 25
        • Rosahl T.W.
        • Spillane D.
        • Missler M.
        • Herz J.
        • Selig D.K.
        • Wolff J.R.
        • et al.
        Essential functions of synapsins I and II in synaptic vesicle regulation.
        Nature. 1995; 375: 488-493
        • Rostas J.A.P.
        • Dunkley P.R.
        Multiple forms and distribution of Ca2+/calmodulin-stimulated protein kinase II in brain.
        J Neurochem. 1992; 59: 1191-1202
        • Saletu B.
        • Anderer P.
        • Assandri A.
        • Prause W.
        • Abu-Bakr M.
        • Lindeck-Pozza E.
        • et al.
        Proving central effects of the nutraceutical and supplementary substance S-adenosyl-L-methionine (ademetionine) by pharmaco-EEG mapping.
        in: Saletu B. Krijzer F. Ferber G. Anderer P. Electrophysiological Brain Research in Preclinical and Clinical Pharmacology and Related Fields—An Update. IPEG, Vienna2000: 182-192
        • Spillmann M.
        • Fava M.
        S-adenosylmethionine in psychi-atric disorders-historical perspective and current aspects.
        CNS Drugs. 1996; 6: 416-425
        • Sudhof T.C.
        The synaptic vesicle cycle.
        Nature. 1995; 375: 645-653
        • Travagli R.A.
        • Gillis R.A.
        • Keller K.J.
        S-Adenosyl-L-methionine modulates firing rate of dorsal motor nucleus of the vagus neurones in vitro.
        Eur J Pharmacol. 1994; 264: 385-390
        • Verona M.
        • Zanotti S.
        • Schäfer T.
        • Racagni G.
        • Popoli M.
        Changes of synaptotagmin interaction with t-SNARE proteins in vitro after calcium/calmodulin-dependent phosphorylation.
        J Neurochem. 2000; 74: 209-221
        • Yokoyama C.T.
        • Sheng Z.-H.
        • Catterall W.A.
        Phosphorylation of the synaptic protein interaction site on N-type calcium channels inhibits interactions with SNARE proteins.
        J Neurosci. 1997; 17: 6929-6938
        • Zanotti S.
        • Mori S.
        • Radaelli R.
        • Perez J.
        • Racagni G.
        • Popoli M.
        Modifications in brain cAMP- and calcium/calmodulin-dependent protein kinases induced by treatment with S-adenosylmethionine.
        Neuropharmacology. 1998; 37: 1081-1089