Folia Pharmacol. Jpn. 122 AMPA AMPA GluR GluR RNA Q R GluR AMPA AMPA GluR AMPA AMPA RNA Q R GluR GluR AMPA AMPA GluR AMPA 1. ATP G - -hydroxy-

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1 Folia Pharmacol. Jpn. 122 AMPA AMPA GluR GluR RNA Q R GluR AMPA AMPA GluR AMPA AMPA RNA Q R GluR GluR AMPA AMPA GluR AMPA 1. ATP G - -hydroxy- -methyl- -isoxazole propionic acid AMPA N-methyl-D-aspartate NMDA kainic acid KA AMPA 2. AMPA AMPA AMPA AMPA GluR GluR GluR GluR AMPA AMPA ALSRNA suzuki-tk@kyoritsu-ph.ac.jp

2 Table 1 Amino acid identities of AMPA receptor subunits among spices and subunits. Identity GluR GluR GluR GluR human-mouse.... mouse-rat.... rat-human.... rat GluR.... rat GluR.... rat GluR.... rat GluR.... Upper part: comparison between human - rat, mouse - rat and rathuman. Lower part: comparison of rat GluR with rat GluR -. Data used for constructing this table were obtained from National Center for Biotechnology Information NCBI, Bethesda, MD with accession numbers, XM- human GluR, Lhuman GluR, XM- human GluR, Uhuman GluR, NM- mouse GluR, NM- mouse GluR, AB mouse GlulR, NM- mouse GluR, Mrat GluR, Mrat GluR, Mrat GluR, andmrat GluR. - GluR - - Table GluR - cdna GluR - -- cdna RNA AMPA AMPA M M Fig. flip flop M M C M M GluR Q R RNA GluR GluR GluR RNA CAG Q GluR RNA CAG CGG R RNA GluR Q R RNA AMPA C C AMPA GRIP PICK SAP AMPA C AMPA 3. AMPA 1 AMPA M Q R GluR

3 AMPA Fig. 1 Structure of AMPA receptor subunits and amino acid sequence of the M segment. The box indicates the Q glutamine R arginine site of the AMPA subunit. AMPA subunits have two RNA editing sites, Q Rsite GluR only and R G site GluR -, and two splicing variants, flip flop GluR - and long form short form GluR and. GluR Q GluR AMPA AMPA GluR AMPA AMPA RT- PCR GluR AMPA mrna RT-PCR GluR mrna GluR AMPA GluR Q Q R GluR RNA GluR Q RNA ALS 2 AMPA Q R Q R AMPA cyclothiazide flip flop flop flip GluR cyclothiazide AMPA

4 mm EPSC 3 AMPA GluR AMPA AMPA Mansour HEK GluR AMPA HEK AMPA GluR AMPA GluR AMPA GluR AMPA GluR AMPA GluR AMPA Q R GluR AMPA GluR RNA Q R GluR Q AMPA 4. AMPA AMPA Excitatory Post- Synaptic Current, EPSC EPSC CA Long Term Potentiation, LTP Long Term Depression, LTD AMPA 1 AMPA AMPA AMPA AMPA G AMPA dynamin clathrin coated vesicle AMPA NMDA NMDA GluR

5 AMPA A PKA S PKA LTD NMDA GluR LTP II CaMKII GluR S LTP LTP LTP AMPA GluR GFP GluR GluR NMDA NR GluR GluR AMPA GluR GluR GluR GluR GluR GluR GluR GluR AMPA GluR GluR GluR Q 2 AMPA AMPA GluR NSF AP NSF ATPase AP Clatrhrin GluR NSF GluR AP NSF AP GluR NSF GluR EPSC LTD AP GluR EPSC LTD EPSC LTD NSF AP GluR NSF GluR AP GluR AP GluR AMPA GluR GluR C- GRIP PICK PDZ GluR C PKC GRIP GluR PICK GluR LTD GluR S GluR PICK PICK LTD

6 Fig. 2 Trafficking of AMPA receptor to synaptic membrane. GluR containing AMPA receptors are transported from the cell body to the dendrite shaft by SAP-. Stargazin is necessary to bring AMPA receptor to synaptic membrane. AMPA receptors consisting of GluR subunits are transported from the cell body to the dendrite by GRIP and KIF complex. NSF is functioning in receptor exocitosis to the synaptoic membrane; on the other hand, AP is affecting the speed of the receptor internalization. After internalization, some receptors are recycled to synaptic membranes, and the other receptors are degradated in the lysosome. GRIP GluR GRIP GluR PDZ KIF A GluR -GRIP-KIF A GluR Band. N SAP SAP PDZ GluR C SAP GluR C PDZ Band. N GluR AMPA Stargazin AMPA AMPA AMPA PSD- PDZ Stargazin PSD- AMPA NMDA PSD- Stargazin AMPA Stargazin PSD-

7 AMPA PKA PSD- AMPA Fig. 5. GluR2 Q R GluR Q R AMPA RNA 1 ALS amyotrophic lateral sclerosis ALS - - ALS ALS ALS superoxide dismutase SOD ALS ALS 2 AMPA ALS ALS AMPA AMPA AMPA AMPA ALS flip flop flop - RT-PCR AMPA mrna GluR RNA ALS ALS AMPA GluR GluR mrna 3 GluR2 Q R ALS GluR Q R GluR mrna Q R RNA Q Q R RNA GluR RNA GluR mrna Q R R GluR Q GluR RNA GluR Q R RNA adenosine deaminases acting on RNA ADAR RNA deaminase AMPA GluR GluR pre-mrna Q R RNA ADARs GluR GluR GluR RNA ADAR RNA GluR R G GluR GluR Q R -HT c RNA GluR Q R

8 Fig. 3 Editing efficiency at the Q R site of GluR mrna in the brain areas that are most extensively affected in degenerative neurological diseases. Significant reduction is demonstrated only in ALS VH... Mann-Whitney test. P.. AD: Alzheimer disease, ALS: amyotrophic lateral sclerosis, Cbl: cerebellum, Cx: cerebral cortex, DH: dorsal horn of the spinal cord, DRPLA: dentatorubral pallidoluysian atrophy, HD: Huntington disease, MJD: Machado-Joseph disease, MSA: multiple system atrophy, Str: striatum, Tcx: temporal cortex, VH ventral horn of the spinal cord. ADARs ADAR GluR mrna Q R ADAR ADAR GluR Q R GluR RNA GluR GluR mrna GluR Q R RNA ALS ALS GluR Q R mrna Fig. - - ALS GluR Q R ALS Q R N minigene ALS minigene GluR N GluR GluR Q AMPA GluR Q R GluR GluR R GluR Q GluR Q AMPA ALS GluR Q AMPA mrna GluR AMPA AMPA ALS

9 AMPA RNA ALS GluR Q R RNA ADAR ADAR ADAR ADAR GluR Q R RNA ADAR GluR RNA ADAR GluR. GluR Q R GluR RNA ADAR mrna ADAR ALS ADAR RNA GluR Q R RNA 6. AMPA AMPA GluR AMPA NMDA AMPA NMDA AMPA AMPA NMDA CA LTP NMDA GluR GluR Q CA AMPA LTP CaMK PKC AKT MAPK camp PKA AMPA AMPA AMPA GluR GluR AMPA GluR AMPA AMPA GluR AMPA AMPA Ozawa S, Kamiya H, Tsuzuki K. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol. ; :-.

10 Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. Mechanism of glutamate receptor desensitization. Nature. ;:-. Kung SS, Chen YC, Lin WH, Chen CC, Chow WY. Q R RNA editing of the AMPA receptor subunit GRIA transcript evolves no later than the appearance of cartilaginous fishes. FEBS Lett. ; :-. Iino M, Ozawa S, Tsuzuki K. Permeation of calcium through excitatory amino acid receptor channels in cultured rat hippocampal neurones. J Physiol Lond. ;:-. Bochet P, Audinat E, Lambolez B, et al. Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel. Neuron. ; :-. Tsuzuki K, Lambolez B, Rossier J, Ozawa S. Absolute quantification of AMPA receptor subunit mrnas in single hippocampal neurons. J Neurochem. ; : -. Partin KM, Patneau DK, Winters CA, Mayer ML, Buonanno A. Selective modulation of desensitization at AMPA versus kainate receptors by cyclothiazide and concanavalin A. Neuron. ; :-. Suzuki T, Brorson JR. Changes in glutamate responses in HEK cells transfected with varied ratios of AMPA receptor subunits. Neurosci Res. ;Sppl :S. Mansour M, Nagarajan N, Nehring RB, Clements JD, Rosenmund C. Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement. Neuron. ; :-. Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. ; :-. Ehlers MD. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron. ; :-. Lee HK, Takamiya K, Han JS, et al. Phosphorylation of the AMPA receptor GluR subunit is required for synaptic plasticity and retention of spatial memory. Cell. ;:-. Shi S, Hayashi Y, Esteban JA, Malinow R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell. ;:-. Greger IH, Khatri L, Ziff EB. RNA editing at arg controls AMPA receptor exit from the endoplasmic reticulum. Neuron. ; :-. Sheng M, Kim MJ. Postsynaptic signaling and plasticity mechanisms. Science. ;:-. Song I, Huganir RL. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. ; :-. Lee SH, Liu L, Wang YT, Sheng M. Clathrin adaptor AP and NSF interact with overlapping sites of GluR and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron. ; : -. Chung HJ, Steinberg JP, Huganir RL, Linden DJ. Requirement of AMPA receptor GluR phosphorylation for cerebellar long-term depression. Science. ;: -. Setou M, Seog DH, Tanaka Y, et al. Glutamatereceptor-interacting protein GRIP directly steers kinesin to dendrites. Nature. ;: -. Chen L, Chetkovich DM, Petralia RS, et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature. ;: -. Chetkovich DM, Chen L, Stocker TJ, Nicoll RA, Bredt DS. Phosphorylation of the postsynaptic density-psd- discs large zona occludens- binding site of stargazin regulates binding to PSD- and synaptic targeting of AMPA receptors. J Neurosci. ; : -. Rosen DR, Siddique T, Patterson, D et al. Mutations in Cu Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. ;: -. Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis. NatGenet. ; :-. Nakamura R, Kamakura K, Kwak S. Late-onset selective neuronal damage in the rat spinal cord induced by continuous intrathecal administration of AMPA. Brain Res. ;:-. Vandenberghe W, Robberecht W, Brorson JR. AMPA receptor calcium permeability, GluR expression, and selective motoneuron vulnerability. J Neurosci. ; :-. Tomiyama M, Rodriguez-Puertas R, Cortes R, Pazos A, Palacios JM, Mengod G. Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis. Synapse. ; :-. Kawahara Y, Kwak S, Sun H, et al. Human spinal motoneurons express low relative abundance of GluR mrna: an implication for excitotoxicity in ALS. J Neurochem. ; :-. Feldmeyer D, Kask K, Brusa R, et al. Neurological dysfunctions in mice expressing different levels of the Q R site-unedited AMPAR subunit GluR-B. Nat Neurosci. ; : -. Lai F, Chen CX, Carter KC, Nishikura K. Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA doublestranded RNA adenosine deaminases. Mol Cell Biol. ; : -. Nutt SL, Kamboj RK. Differential RNA editing efficiency of AMPA receptor subunit GluR- in human brain. Neuroreport. ; : -. Seeburg PH, Single F, Kuner T, Higuchi M, Sprengel R. Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse. Brain Res. ;:-. Sommer B, Kohler M, Sprengel R, Seeburg PH. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell. ; : -. Higuchi M, Single FN, Kohler M, Sommer B, Sprengel R, Seeburg PH. RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon

11 AMPA structure determines position and efficiency. Cell. ; : -. Maas S, Melcher T, Herb A, et al. Structural requirements for RNA editing in glutamate receptor pre-mrnas by recombinant double-stranded RNA adenosine deaminase. J Biol Chem. ;: -. Higuchi M, Maas S, Single FN, et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR. Nature. ;: -. Paschen W, Hedreen JC, Ross CA. RNA editing of the glutamate receptor subunits GluR and GluR in human brain tissue. J Neurochem. ; : -. Akbarian S, Smith MA, Jones EG. Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer s disease, Huntington s disease and schizophrenia. Brain Res. ;:-. Maas S, Patt S, Schrey M, Rich A. Underediting of glutamate receptor GluR-B mrna in malignant gliomas. Proc Natl Acad Sci USA. ; : -. Kawahara Y, Ito K, Sun H, Kanazawa I, Kwak S. Low editing efficiency of GluR mrna is associated with a low relative abundance of ADAR mrna in white matter of normal human brain. Eur J Neurosci. ; : -. Kwak S, Takuma H, Kanazawa I. Molecular changes of AMPA receptor subunits in ALS spinal cord. In: Abe K, editor. Molecular Mechanism and Therapeutics of Amyotrophic Lateral Sclerosis. Amsterdam: Elsevier Science BV;. P.-. Takuma H, Kwak S, Yoshizawa T, Kanazawa I. Reduction of GluR RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann Neurol. ; :-. Jia Z, Agopyan N, Miu P, et al. Enhanced LTP in mice deficient in the AMPA receptor GluR. Neuron. ; :-. Okada T, Yamada N, Kakegawa W, et al. Sindbis viral-mediated expression of Ca -permeable AMPA receptors at hippocampal CA synapses and induction of NMDA receptor-independent longterm potentiation. Eur J Neurosci. ; : -. Iino M, Goto K, Kakegawa W, et al. Glia-synapse interaction through Ca -permeable AMPA receptors in Bergmann glia. Science. ;:-. Ishiuchi S, Tsuzuki K, Yoshida Y, et al. Blockage of Ca -permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med. ; :-. Abstract Recent advances in the study of AMPA receptors. Takeshi SUZUKI, Keisuke TSUZUKI, Kimihiko KAMEYAMA, and Shin KWAK Dept. Pharmacol, Kyoritsu Coll. Pharm., Minato-ku, Tokyo -, Japan; Dept. Neurophysiol., Gunma Univ., Maebashi-, Japan; Mol. Neurophysiol., Neurosci. Inst. AIST, Tsukuba-city, Ibaraki -, Japan; Dept. Neurol., Univ. Tokyo, Bunkyo-ku, Tokyo -, Japan. Folia Pharmacol. Jpn. Nippon Yakurigaku Zasshi 122, As glutamate is a dominant excitatory neurotransmitter in the central nervous system, glutamate receptors, and especially AMPA receptors, are located ubiquitously in all brain areas. In this paper, we reviewed recent advances of studies on AMPA receptor functions. AMPA receptors are cation-conducting complexes composed of various combinations of four subunits GluR to GluR. The glutamine residue located in the pore-forming segment of GluR subunit Q R site is changed to arginine by RNA editing at the pre mrna stage in normal adult mammalian animal. The edited GluR subunit is a major determination of Ca permeability of the AMPA receptor; only edited GluR -lacking receptor shows high-ca permeability. The assembly of glutamate AMPA receptor subunit is not completely according to the stochastic theory. The heteromeric subunits assembly is more rapid than the homomeric assembly is. The transfer of AMPA receptor subunit to the plasma membrane is conducted in multiple ways. Many molecules that interact with the intracellular domain of AMPA receptor subunits are reported as the modulators of AMPA receptor subunit transfer. In the motoneuron of sporadic amyotrophic lateral sclerosis ALS patients, the efficiency of RNA editing at the GluR Q R site is significantly decreased. Relative low level of edited GluR subunit expression is likely responsible for motoneuronal death in ALS. Recently, AMPA receptors in glial cells have been studied. Bergmann glial cells in cerebellum express Ca -permeable AMPA receptors. Conversion of these AMPA receptors to Ca -impermeable type receptors induces morphological and functional changes. Glioblastoma cells also express Ca -permeable AMPA receptors, and their conversion to Ca - impermeable receptors inhibits cell locomotion and induces apoptosis. Keywords: AMPA receptor; amyotrophic lateral sclerosis ALS ; calcium; glutamate; RNA editing

12 Dr Brorson Ca AMPA Johns Hopkins AMPA RNA

平成１４年度本態性多種化学物質過敏状態の調査研究研究報告書

平成１４年度本態性多種化学物質過敏状態の調査研究研究報告書 226 227 µ 228 Ω 229 230 0 ppb 2000ppb DG subthreshold (µa) 91 ± 59 86 ± 68 max stim. (µa) 755 ± 287 n=37 678 ± 300 max PS (mv) 8.7 ± 3.9 7.7 ± 4.3 n=61 CA1 subthreshold (µa) 36 ± 26 32 ± 13 max stim. (µa)