摘要
细胞内钙离子浓度对于维持正常的神经元功能有着重要作用。研究表明,钙离子的多种功能都必须通过钙结合蛋白以及其与靶蛋白的互作来介导,神经元钙感应蛋白(Neuronal Calcium Sensors,NCS)家族是其中非常重要的一组。
神经元钙感应蛋白家族属于EF-hand类Ca~(2+)结合蛋白超家族中的一个亚家族,在进化过程中高度保守,典型的结构特征是均含有3-4个EF-hand的Ca~(2+)结合功能域。迄今为止已有20多个不同物种的NCS蛋白被克隆,分属3个亚类,第1类包括visinin、recoverin和S-modulin;第2类包括hippocalcin、frequenin和NCS-1;第3类为4个新克隆的KChIP蛋白,KChIP1-4。KChIPs不同成员之间的相似性非常高,在氨基酸水平的相似性达到65%,其C端为3-4个EF-hand,N端的差异较大。
KChIPs能与A型钾离子通道Kv4相互作用,发挥A型快钾通道的β亚基的功能。KChIP1能减缓Kv4.2的失活时程,但却显著加速Kv4.1的失活。小鼠基因组中剔除KChIP2可导致心肌细胞Ca~(2+)依赖的短暂外向K~+离子电流完全丢失,KChIP2剔除小鼠表现为室性心动过速,进一步说明了KChIPs有调节K~+离子通道的作用。KChIP3可以同Kv4.2、Kv4.3和Kv4.4通道相互作用,调节K+通道电流,从而在长程增强和神经元塑性中发挥重要的作用。KChIP4同样具有同Kv4.2和Kv4.3通道相互作用的能力,突变KChIP4的Ca~(2+)结合模体可造成K+通道电导消失。
KChIPs在细胞内还可以与多种蛋白发生相互作用,我们在过去的研究中,用酵母双杂交技术研究家族性大肠腺瘤息肉病致病基因APC(APC,Adenomatous polyposis coli)的中段互作蛋白过程中独立克隆了KChIP1,提示KChIP1可能参与APC介导的神经性调控。KChIP3可以同老年性痴呆(Alzheimer's Disease,AD)相关蛋白早老素presenilin结合;体外实验及KChIP3-/-小鼠体内实验均证实,其还可以与强啡肽反应元件(DynorphinResponse Element,DRE)结合,抑制性调节Prodynorphin的表达,从而调节痛觉反应,因此又被称为DREAM。此外,KChIP3还具有钙依赖性的凋亡刺激作用和寡聚化作用。同样,KChIP4也能与老年性痴呆相关基因早老素2(presenilin-2)相互作用,当KChIP4单独表达时呈胞浆和核弥散性分布,与presenilin-2共同表达时会发生核周和内质网上的共定位。
尽管已经有了上述这些发现,但KChIPs蛋白家族在其主要表达部位—脑的功能仍不清楚。本研究在前人的基础上,对KChIP1基因在脑内的功能进行了深入地研究。整个研究分为3个部分。
第一部分通过组织原位杂交、免疫组化以及免疫染色研究,我们发现在成年小鼠脑中,KChIP1主要表达在一组小清蛋白(parvalbumin)阳性的GABA(gamma amino butyric acid,γ-氨基丁酸,GABA)能神经元,GABA传导抑制性突触传递,提示KChIP1可能在调节抑制性突触传递中起作用。
第二部分;我们通过基因打靶、同源重组技术对KChIP1基因进行了敲除,得到了KChIP1+/-和KChIP1-/-突变小鼠。杂合子和纯合子小鼠在出生、发育等方面与野生型小鼠无显著差异,并且符合孟德尔遗传规律,提示KChIP1基因在小鼠胚胎发育中是非必须的,并且KChIP1基因对于小鼠出生后的生长发育也无显著的影响。尽管如此,我们还是发现了一些有趣的现象:KChIP1+/-和KChIP1-/-小鼠做转轮实验(Rotarod test)时较野生型小鼠更容易从转轮中摔落下来(P＜0.05),提示其存在潜在的运动功能障碍;通过使用戊四氮(Pentylenetetrazole,PTZ)诱导癫痫发作,我们发现KChIP1+/-和KChIP1-/-小鼠较野生型小鼠更容易发生抽搐,并且致死率很高(P＜0.05),进一步提示了KChIP1在调节抑制性突触传递中的生理学作用。
第三部分中,我们在KChIP1-/-突变小鼠的小脑组织中,克隆了一种新的KChIP1剪切体,我们命名为KChIP1c。先前的研究表明KChIP1具有两个剪切变异体,称为KChIP1a和KChIP1b,后者N端包含另外一个外显子。与KChIP1a和KChIP1b相似,在细胞水平,KChIP1c能与Kv4.3互作,并促进Kv4.3的膜定位。在爪蟾的卵母细胞中,KChIP1c能增加Kv4.3电流的振幅,加速其在开放状态下的失活,促进其在失活状态下的快速恢复。然而,与KChIP1a和KChIP1b相比,KChIP1c比KChIP1a、KChIP1b更能增加Kv4.3电流的振幅,而且KChIP1c并不影响Kv4.3在关闭状态下的失活。
综上所述,通过上述研究,我们得出以下结论:KChIP1通过与细胞中Kv4.2和Kv4.3离子通道相互作用,引起细胞的兴奋性发生改变,从而在调节机体运动平衡中发挥一定的作用;KChIP1通过与GABAergic神经元细胞上的Kv4.2和Kv4.3通道相互作用,促进GABA神经递质的释放,从而在对抗癫痫发作、维持神经系统的兴奋性状态中发挥重要的作用;在脑内存在着不同的KChIP1,其功能也不尽相同,在不同的部位对A型钾离子通道起着不同的调节作用。以上结果为KChIP1相关退行性疾病诊断和治疗研究奠定了良好的理论基础。
It is well known Ca~(2+) plays an important role in regulating a variety of neuronal processes, such as neurotransmission, cytoskeletal dynamics, gene expression and signal transduction. The actions of Ca~(2+) are often mediated by Ca~(2+)- binding proteins, which may act as either Ca~(2+) buffers or Ca~(2+) sensors. Neuronal Calcium Sensor (NCS) is a large family of Ca~(2+)-binding proteins, and is very important in modulating the Ca~(2+) mediated signals transduction.
More than 20 NCS proteins have been identified from various species. These proteins are highly conserved through out the evolution, sharing high homolog within their C-terminal. One important structural feature of NCS is containing four EF-Hand calcium binding motifs in each protein. NCS proteins can be classified into three subclasses. ClassⅠ, includes visinin, recoverin and S-modulin. ClassⅡ, consists of hippocalcin, frequenin, and NCS-1. The four newly identified KChIP proteins constitute the third class. KChIPs share more than 65% identity at the amino acid level with a distinct N-terminus.
KChIPs can interact with A-type potassium channels (Kv4 channels), acting as theβsubunit of fast transient A-type potassium channels. KChIP1 can slow the inactivation period of Kv4.2, while speed this period of Kv4.1. Targeting deletion of KChIP2 gene in mouse genome leads to a complete loss of calcium-dependent transient outward potassium current in cardiac myocytes and confers susceptibility to ventricular tachycardia, which further supports a role of KChIPs in modulating potassium channels. KChIP3 can interact with Kv4.2、Kv4.3and Kv4.4, regulating the kinetic properties of Kv4 channels. KChIP4 also can interact with Kv4.2and Kv4.3. Mutation in the Ca~(2+) binding motif of KChIP4 results in a complete loss of potassium current.
Nevertheless, KChIPs may function in vivo with many other proteins. In our previous study, we used the medium fragment of APC( Adenomatous polyposis coli) as the bait to screen the human fetal brain cDNA library by Yeast Two Hybrid and identified KChIP1, suggesting its role in APC related neuronal regulation. KChIP3 is referred to calsenilin for its interaction with Alzheimer's disease related presenilin-2, although the functional significance of these interactions remains to be elucidated. KChIP3 is also called DREAM, a downstream regulatory element antagonist modulator. DREAM (KChIP3)-deficient mice exhibit reduced responses in models of acute pain through a transcriptional mechanism. Upon single transfection, KChIP4 was diffusely distributed in cytoplasm as well as in nuclei. Double transfection with PS2 dramatically changed the distribution of KChIP4 into a reticular pattern, overlapping with that of PS2 in the perinuclear area and endoplasmic reticulum membranes, supporting KChIP4 interaction with presenilin-2.
Preliminary study has demonstrated that KChIPs is an important protein with multifunction, however, the function of KChIP proteins in brain where they are predominantly expressed remains unclear. To answer this question, the function of KChIP1 in brain was carried out in this study. The study has 3 parts.
In the first part, by in situ hybridization, immunohistochemical assay and immunostaining, we found KChIP1 is predominantly expressed in a subpopulation of parvalbumin-positive GABAergic neurons in mouse brain, suggesting its functional relationship with GABAergic inhibitory neurons.
In the second part, we deleted the KChIP1 gene in mouse genome by a targeting construct. The fact that no embryonic lethality or significant difference in brain and weight was observed in these mice compared with their wild-type littermates hinted that KChIP1 may be not requisite for embryo growth and development. However, the mice bearing KChIP1 deletion showed impaired motor coordination, suggesting that KChIP1 may play important roles in controlling motor function. Moreover, the mutant mice showed increased susceptibility to anti-GABAergic convulsive drug-PTZ-induced seizure, further supporting its roles in synaptic transmission of GABAergic inhibitory neurons.
In the third part, in the mutant mouse brain, we identified a novel Purkinje neuron-specific KChIP1 splicing variant, KChIP1c. KChIP1c has a distinct N-terminus from KChIP1a and KChIP1b that is encoded by an alternative exon. Like KChIP1a and KChIP1b, KChIP1c interacts with Kv4.3 and promotes the plasma membrane localization of Kv4.3 in transfected cells. In Xenopus oocytes, KChIP1c enhanced Kv4.3 currents amplitude that is significantly larger than those caused by KChIP1a and KChIP1b. In contrast, KChIP1c did not affect the inactivation of Kv4.3 in its closed state. The results suggest that KChIP1c may function in modulating Kv4.3 currents with a mechanism different from KChIP1a and KChIP1b.
In summary, our results suggested: KChIP1 can change cells' excitability through interaction with potassium channel protein Kv4.2 and Kv4.3, therefore regulating balance; KChIP1 can also modulate inhibitory synaptic transmission through increasing presynaptic GABA release, which may play an important role in the anti-epileptic attack and the maintenance of the normal nervous status; Different KChIP1s, differently distributed, may function differently in regulating A-type potassium channels. These results may provide useful basis in diagnosis and treatment of KChIP1 related degenerative diseases.
引文
1. Yamagata, K., Goto, K., Kuo, C. H., Kondo, H., and Miki, N.. Visinin: a novel calcium binding protein expressed in retinal cone cells. Neuron, 1990, 4: 469-476.
2. Dizhoor, A. M., Ray, S., Kumar, S., Niemi, G, Spencer, M, Brolley, D., Walsh, K. A., Philipov, P. P., Hurley, J. B., and Stryer, L. Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Science, 1991, 251: 915-918.
3. Kawamura, S., Takamatsu, K., and Kitamura, K. Purification and characterization of S-modulin, a calcium-dependent regulator on cGMP phosphodiesterase in frog rod photoreceptors. Biochem Biophys Res Commun,1992,186:411-417.
4. Kobayashi, M., Takamatsu, K., Saitoh, S., Miura, M., and Noguchi, T. Molecular cloning of hippocalcin, a novel calcium-binding protein of the recoverin family exclusively expressed in hippocampus. Biochem Biophys Res Commun, 1992,189:511-517.
5. Pongs,O., Lindemeier, J., Zhu, X. R., Theil, T., Engelkamp, D., Krah-Jentgens, I., Lambrecht, H. G., Koch, K. W., Schwemer, J., Rivosecchi, R., and et al. Frequenin~a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system. Neuron, 1993, 11: 15-28.
6. Gomez, M., De Castro, E., Guarin, E., Sasakura, H., Kuhara, A., Mori, I., Bartfai, T., Bargmann, C. I., and Nef, P.. Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans. Neuron, 2001,30:241-248.
7. Olafsson P, Wang T, and Lu B. Molecular Cloning and Functional Characterization of the Xenopus Ca~(2+)-Binding Protein Frequenin. PNAS, 1995, 92: 8001-8005.
8. Angaut-Petit, D., Toth, P., Rogero, O., Faille, L., Tejedor, F. J., and Ferrus, A. Enhanced neurotransmitter release is associated with reduction of neuronal branching in a Drosophila mutant overexpressing frequenin. Eur J Neurosci, 1998,10:423-434.
9. Genin, A., Davis, S., Meziane, H., Doyere, V., Jeromin, A., Roder, J., Mallet, J., and Laroche, S. Regulated expression of the neuronal calcium sensor-1 gene during long-term potentiation in the dentate gyrus in vivo. Neuroscience,2001,106:571-577.
10. McFerran, B. W., Graham, M. E., and Burgoyne, R. D. Neuronal Ca2+ sensor 1, the mammalian homologue of frequenin, is expressed in chromaffin and PC 12 cells and regulates neurosecretion from dense-core granules. J Biol Chem, 1998,273:22768-22772.
11. Burgoyne, R. D., and Weiss, J. L. The neuronal calcium sensor family of Ca2+-binding proteins. Biochem J, 2001,353: 1-12
12. An, W. F., Bowlby, M. R., Betty, M., Cao, J., Ling, H. P., Mendoza, G, Hinson, J.W., Mattsson, K. I., Strassle, B. W., Trimmer, J. S., and Rhodes, K. J.. Modulation of A-type potassium channels by a family of calcium sensors. Nature, 2000,403:553-556.
13. Burgoyne RD. Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+signalling. Nat Rev Neurosci. 2007, 8(3):182-193.
14. Nakamura TY, Nandi S, Pountney DJ, Artman M, Rudy B, Coetzee WA.,Different effects of the Ca(2+)-binding protein, KChIP1, on two Kv4 subfamily members, Kv4.1 and Kv4.2, FEBS Lett. 2001,499(3):205-9.
15. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguyen-Tran VT, Gu Y, Ikeda Y, Chu PH, Ross J, Giles WR, Chien KR. A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell, 2001,107:801-813.
16. Holmqvist MH, Cao J, Hernandez-Pineda R, Jacobson MD, Carroll KI, Sung MA, Betty M, Ge P, Gilbride KJ, Brown ME, Jurman ME, Lawson D, Silos-Santiago I, Xie Y, Covarrubias M, Rhodes KJ, Distefano PS, An WF.Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain. Proc Natl Acad Sci U S A, 2002, 99(2): 1035-40
17. Midgley CA, White S, Howitt R, Save V, Dunlop MG, Hall PA, Lane DP, Wyllie AH, Bubb VJ .APC expression in normal human tissues. J Pathol, 1997,181(4): 426-33
18. Bhat R V, Baraban J M, Johnson RC, Eipper BA, Mains RE. High levels of expression of the tumor suppressor gene APC during development of the rat central nervous system. J Neurosci, 1994 ,14(5 Pt 2): 3059-71
19. Brakeman JS, Gu SH, Wang XB, Dolin G, Baraban JM. Neuronal localization of the Adenomatous polyposis coli tumor suppressor protein. Neuroscience, 1999,91(2): 661-72
20. Dobashi Y, Katayama K, Kawai M, Akiyama T, Kameya T. APC protein is required for initiation of neuronal differentiation in rat pheochromocytoma PC 12 cells. Biochem Biophys Res Commun, 2000,279(2): 685-91
21. Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, Aoki T, Arakawa H, Yanagisawa A, Ushio Y. Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosomes Cancer, 1994, 9(3): 168-72
22. Leroy K, Duyckaerts C, Bovekamp L, M(?)ller O, Anderton BH, Brion JP. Increase of adenomatous polyposis coli immunoreactivity is a marker of reactive astrocytes in Alzheimer's disease and in other pathological conditions. Acta Neuropathol (Berl), 2001,102(1): 1-10
23. Carrion AM, Link WA, Ledo F, Mellstrom B, Naranjo JR. DREAM is a Ca2+-regulated transcriptional repressor.Nature. 1999, 398(6722):80-84.
24. Spreafico F, Barski JJ, Farina C, Meyer M. Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression. Mol Cell Neurosci. 2001,
25. Carrion AM, Mellstrom B, Naranjo JR. Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. Mol Cell Biol. 1998,18(12):6921-6929.
26. Cheng HY, Pitcher GM, Laviolette SR, Whishaw IQ, Tong KI, Kockeritz LK, Wada T, Joza NA, Crackower M, Goncalves J, Sarosi I, Woodgett JR, Oliveira-dos-Santos AJ, Ikura M,van der Kooy D, Salter MW, Penninger JM. DREAM is a critical transcriptional repressor for pain modulation. Cell. 2002,108(1):31-43.
27. Costigan M, Woolf CJ. No DREAM, No pain. Closing the spinal gate. Cell. 2002,108(3):297-300.
28. Jo DG, Chang JW, Hong HS, Mook-Jung I, Jung YK. Contribution of presenilin/gamma-secretase to calsenilin-mediated apoptosis. Biochem Biophys Res Commun. 2003, 305(1):62-66.
29. Jo DG, Kim MJ, Choi YH, Kim IK, Song YH, Woo HN, Chung CW, Jung YK. Pro-apoptotic function of calsenilin/DREAM/KChIP3. FASEB J. 2001, 15(3):589-591.
30. Lilliehook C, Chan S, Choi EK, Zaidi NF, Wasco W, Mattson MP, Buxbaum JD. Calsenilin enhances apoptosis by altering endoplasmic reticulum calcium signaling. Mol Cell Neurosci.2002, 19(4):552-559.
31. Ledo F, Kremer L, Mellstrom B, Naranjo JR. Ca2+-dependent block of CREB-CBP transcription by repressor DREAM. EMBO J. 2002,21(17):4583-4592.
32. Mellstrom B, Naranjo JR. Ca2+-dependent transcriptional repression and derepression:DREAM, a direct effector. Semin Cell Dev Biol. 2001, 12(1):59-63.
33. . Osawa M, Tong KI, Lilliehook C, Wasco W, Buxbaum JD, Cheng HY, Penninger JM, Ikura M, Ames JB. Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein,calsenilin/DREAM/KChIP3. J Biol Chem. 2001,276(44):41005-41013.
34. Xiong H, Kovacs I, Zhang Z. Differential distribution of KChlPs mRNAs in adult mouse brain. Molecular Brain Research. 2004, 128:103-111.
35. Celio, M. R. Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience, 1990, 35: 375-475.
36. DeFelipe, J. Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. J Chem Neuroanat, 1997,14: 1-19.
37. Gonchar, Y., and Burkhalter, A. Differential subcellular localization of forward and feedback interareal inputs to parvalbumin expressing GABAergic neurons in rat visual cortex. J Comp Neurol, 1999,406: 346-360.
38. Arvidsson, U., Riedl, M., Elde, R., and Meister, B. Vesicular acetylcholine transporter (VAChT) protein: a novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol, 1997,378: 454-467.
39. Smith, Y, Seguela, P., and Parent, A. Distribution of GABA-immunoreactive neurons in the thalamus of the squirrel monkey (Saimiri sciureus). Neuroscience,1987,22:579-591.
40. Cicchetti, F., Prensa, L., Wu, Y, and Parent, A. Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington's disease. Brain Res Brain Res Rev, 2000,34: 80-101.
41. Meade, C. A., Deng, Y. P., Fusco, F. R., Del Mar, N., Hersch, S., Goldowitz, D., and Reiner, A. Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice. J Comp Neurol, 2002,449: 241-269.
42. Guentchev, M., Groschup, M. H., Kordek, R., Liberski, P. P., and Budka, H. Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies. Brain Pathol, 1998,8:615-623.
43. Guentchev, M., Wanschitz, J., Voigtlander, T., Flicker, H., and Budka, H. Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am J Pathol, 1999,155: 1453-1457.
44. Eyles, D. W., McGrath, J. J., and Reynolds, G. P. Neuronal calcium-binding proteins and schizophrenia. Schizophr Res, 2002, 57: 27-34.
45. Reynolds, G. P., Beasley, C. L, and Zhang, Z. J. Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. J Neural Transm, 2002,109: 881-889.
46. Zhang, Z. J., and Reynolds, G. P. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia.Schizophr Res, 2002, 55: 1-10.
47. Saudou, F., Finkbeiner, S., Devys, D., and Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell, 1998, 95: 55-66.
1. Li Y, Urn SY, McDonald TV. Voltage-gated potassium channels: regulation by accessory subunits. Neuroscientist. 2006,199-210.
2. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ Modulation of A-type potassium channels by a family of calcium sensors. Nature, 2000, 403:553-556.
3. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguy(?)(?)-Tr(?)n VT, Gu Y, Ikeda Y,Chu PH, Ross J, Giles WR, Chien KR. A defect in the Kv hannel-interacting protein 2(KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventriculartachycardia. Cell. 2001, 107(6):801-813.
4. Ren X, Shand SH, Takimoto K. Effective association of Kv channel-interacting proteins with Kv4 channel is mediated with their unique core peptide. J Biol Chem. 2003 ;278(44):43564-43570.
5. Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, McKinnon D. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol. 2001, 533(Pt1):119-125.
6. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, Nerbonne JM. Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ Res.2002, 90(5):586-593.
7. B(?)hring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D. Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001, 276(26):23888-22394.
8. Lin YL, Chen CY, Cheng CP, Chang LS. Protein-protein interactions of KChIP proteins and Kv4.2. Biochem Biophys Res Commun. 2004, 321(3):606-610.
9. Buxbaum JD. A role for calsenilin and related proteins in multiple aspects of neuronal function. Biochem Biophys Res Commun. 2004, 322(4): 1140-1144
10. Shibata R, Misonou H, Campomanes CR, Anderson AE, Schrader LA, Doliveira LC, CarrollKI, Sweatt JD, Rhodes KJ, Trimmer JS. A fundamental role for KChIPs in determining themolecular properties and trafficking of Kv4.2 potassium channels. J Biol Chem. 2003,278(38):36445-36454.
11. Patel SP, Parai R, Parai R, Campbell DL. Regulation of Kv4.3 voltage-dependent gatingkinetics by KChIP2 isoforms. J Physiol. 2004, 557(Pt
12. Holmqvist MH, Cao J, Hernandez-Pineda R, Jacobson MD, Carroll KI, Sung MA, Betty M,Ge P, Gilbride KJ, Brown ME, Jurman ME, Lawson D, Silos-Santiago I, Xie Y, Covarrubias M, Rhodes KJ, Distefano PS, An WF. Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain. Proc Natl Acad Sci USA. 2002,
13. Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y. Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2. Biochem Biophys Res Commun. 2001,282(1):96-102.
14. Holmqvist MH, Cao J, Knoppers MH, Jurman ME, Distefano PS, Rhodes KJ, Xie Y, An WF.Kinetic modulation of Kv4-mediated A-current by arachidonic acid is dependent on potassium channel interacting proteins. J Neurosci. 2001,21(12):4154-4161.
15. Buxbaum JD, Choi EK, Luo Y, et al. Calsenilin: a calcium-binding protein that interacts withthe presenilins and regulates the levels of a presenilin fragment. Nature Medicine. 1998,4(10):l 177-1181.
16. Carrion AM, Link WA, Ledo F, et al. DREAM is a Ca2+-regulated transcriptional repressor.Nature. 1999, 398(6722):80-84.
17. Spreafico F, Barski JJ, Farina C, Meyer M. Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression. Mol Cell Neurosci. 2001,
18. Carrion AM, Mellstr(?)m B, Naranjo JR. Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. Mol Cell Biol. 1998, 18(12):6921-6929.
19. Cheng HY, Pitcher GM, Laviolette SR, Whishaw IQ, Tong KI, Kockeritz LK, Wada T, Joza NA, Crackower M, Goncalves J, Sarosi I, Woodgett JR,liveira-dos-Santos AJ, Ikura M, van der Kooy D, Salter MW, Penninger JM. DREAM is a critical transcriptional repressor for pain modulation. Cell. 2002,108(1):31-43.
20. Costigan M, Woolf CJ. No DREAM, No pain. Closing the spinal gate. Cell. 2002, 108(3):297-300.
21. Jo DG, Jang J, Kim BJ, Lundkvist J, Jung YK. Overexpression of calsenilin enhances gamma-secretase activity. Neurosci Lett. 2005, 378(l):59-64.
22. Bal T, von Krosigk M, McCormick DA. Synaptic and membrane mechanisms underlying synchronized oscillations in the ferret lateral geniculate nucleus in vitro. J Physiol. 1995,483( Pt 3):641-663.
23. Contreras D, Curr6 Dossi R, Steriade M. Electrophysiological properties of cat reticular thalamic neurones in vivo. J Physiol. 1993, 470:273-294.
24. McCormick DA. GABA as an inhibitory neurotransmitter in human cerebral cortex. J Neurophysiol. 1989, 62(5): 1018-1027.
25. Nicoll RA, Malenka RC, Kauer JA. Functional comparison of neurotransmitter eceptorsubtypes in mammalian central nervous system. Physiol Rev. 1990,70(2):513-565.
26. Soltesz I, Crunelli V. GABAA and pre- and post-synaptic GABAB receptor-mediated responses in the lateral geniculate nucleus. Prog Brain Res. 1992,90:151-169.
27. Kim U, Sanchez-Vives MV, McCormick DA. Functional dynamics of GABAergic inhibitionin the thalamus. Science. 1997, 278(5335):130-134.
28. Amabeoku GJ, Chikuni O. Effects of some GABAergic agents on quinine-induced seizures in mice. Experientia. 1992,48(7):659-662.
29. Amabeoku GJ, Farmer CC. Gamma-aminobutyric acid and mefloquine-induced seizures in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2005,29(6):917-921.
30. Su T, Cong WD, Long YS, Luo AH, Sun WW, Deng WY and Liao WP. Altered expression of voltage-gated potassium channel 4.2 and voltage-gated potassium channel 4-interacting protein, and changes in intracellular calcium levels following lithium-pilocarpine-induced status epilepticus. Neuroscience 2008, 157: 566 - 576.
31. Madeja M, Musshoff U, Lorra C, Pongs O and Speckmann EJ.Mechanism of action of the epileptogenic drug pentylenetetrazol on a cloned neuronal potassium channel. Brain Res 1996, 722:59 - 70.
32. Qu L, Liu X, Wu C, Leung LS. Hyperthermia decreases GABAergic synaptic transmission in hippocampal neurons of immature rats. Neurobiol Dis. 2007,27(3):320-327.
33. Johnston D, Christie BR, Frick A, Gray R, Hoffman DA, Schexnayder LK and Watanabe S, et al. Active dendrites, potassium channels and synaptic plasticity. Philos Trans R Soc Lond B Biol Sci 2003, 358:667 - 674.
34. Bernard C, Anderson A, Becker A, Poolos NP, Beck H and Johnston D. Acquired dendritic channelopathy in temporal lobe epilepsy. Science 2004, 305: 532 - 535.
35. Monaghan MM, Menegola M, Vacher H, Rhodes KJ and Trimmer JS.Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy. Neuroscience 2008, 156:550 - 562.
36. Hille B. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, Mass: Sinauer Associates, 1992
37. Connor JA, Stevens CF. Voltage clamp studies of a transient outward membrane current ingastropod neural somata. J Physiol. 1971,213(1):21-30.
38. Byrne JH. Quantitative aspects of ionic conductance mechanisms contributing to firing pattern of motor cells mediating inking behavior in Aplysia californica. J Neurophysiol. 1980, 43(3):651-668.
39. Getting PA. Mechanisms of pattern generation underlying swimming in Tritonia.Ⅲ. Intrinsic and synaptic mechanisms for delayed excitation. J Neurophysiol. 1983,49(4):1036-1050.
40. Ser(?)dio P, Vega-Saenz de Miera E, Rudy B. ,Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain. J Neurophysiol. 1996, 75(5):2174-2179.
41. Ohya S, Tanaka M, Oku T, Asai Y, Watanabe M, Giles WR, Imaizumi Y. Molecular cloning and tissue distribution of an alternatively spliced variant of an A-type K+ channel alpha-subunit, Kv4.3 in the rat. FEBS Lett. 1997,420(1):47-53.
42. Tsaur ML, Chou CC, Shih YH, Wang HL. Cloning, expression and CNS distribution of Kv4.3, an A-type K+ channel alpha subunit. FEBS Lett. 1997, 400(2):215-220.
43. Tsaur ML, Sheng M, Lowenstein DH, Jan YN, Jan LY. Differential expression of K+ channel mRNAs in the rat brain and down-regulation in the hippocampus following seizures. Neuron. 1992, 8(6): 1055-1067.
44. Monaghan MM, Menegola M, Vacher H, Rhodes KJ, Trimmer JS , Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy. Neuroscience.2008,156(3):550-62.
1. Burgoyne RD, Weiss JL.The neuronal calcium sensor family of Ca2+-binding proteins. Biochem J. 2001, 353(Pt 1):1-12.
2. Ohya S, Morohashi Y, Muraki K, Tomita T, Watanabe M, Iwatsubo T, Imaizumi Y. Molecular cloning and expression of the novel splice variants of K(+) channel-interacting protein 2.Biochem Biophys Res Commun. 2001, 282(1):96-102.
3. Holmqvist MH, Cao J, Knoppers MH, Jurman ME, Distefano PS, Rhodes KJ, Xie Y, An WF. Kinetic modulation of Kv4-mediated A-current by arachidonic acid is dependent on potassium channel interacting proteins. J Neurosci. 2001, 21(12):4154-4161.
4. Van Hoorick D, Raes A, Keysers W, Mayeur E, Snyders DJ. Differential Modulation of Kv4 kinetics by KChlPl splice variants. Mol Cell Neurosci. 2003, 24(2):357-366.
5. Boland LM, Jiang M, Lee SY, Fahrenkrug SC, Harnett MT, O'Grady SM. Functional properties of a brain-specific NH2-terminally spliced modulator of Kv4 channels. Am J Physioi Cell Physiol. 2003, 285(1):C 161-170.
6. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, Nguy(?)(?)--Tr(?)n VT, Gu Y, Ikeda Y,Chu PH, Ross J, Giles WR, Chien KR. A defect in the Kv channel-interacting protein 2(KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell. 2001, 107(6):801-813.
7. Patel SP, Parai R, Parai R, Campbell DL. Regulation of Kv4.3 voltage-dependent gating kinetics by KChIP2 isoforms. J Physiol. 2004, 557(Pt 1):19-41.
8. Rosati B, Pan Z, Lypen S, Wang HS, Cohen I, Dixon JE, McKinnon D. Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle. J Physiol. 2001, 533(Pt 1):119-125
9. Bahring R, Dannenberg J, Peters HC, Leicher T, Pongs O, Isbrandt D. Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating. J Biol Chem. 2001, 276(26):23888-22394.
10. Carrion AM, Mellstr(?)m B, Naranjo JR. Protein kinase A-dependent derepression of the human prodynorphin gene via differential binding to an intragenic silencer element. Mol Cell Biol. 1998, 18(12):6921-6929
11. Buxbaum JD, Choi EK, Luo Y, et al. Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nature Medicine. 1998,4(10): 1177-1181.
12. Spreafico F, Barski JJ, Farina C, Meyer M. Mouse DREAM/calsenilin/KChIP3: gene structure, coding potential, and expression. Mol Cell Neurosci. 2001,
13. Liss B, Franz O, Sewing S, Bruns R, Neuhoff H, Roeper J. Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription. Embo J, 2001, 20:5715-5724.
14. Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T, Iwatsubo T. Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4. J Biol Chem. 2002, 26;277(17): 14965-14975.
15. Holmqvist MH, Cao J, Hernandez-Pineda R, Jacobson MD, Carroll KI, Sung MA, Betty M,Ge P, Gilbride KJ, Brown ME, Jurman ME, Lawson D, Silos-Santiago I, Xie Y, Covarrubias M, Rhodes KJ, Distefano PS, An WF. Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain. Proc Natl Acad Sci USA. 2002,99(2):1035-1040.
16. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ. Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000, 403(6769):553-556.
17. Zozulya S, Stryer L. Calcium-myristoyl protein switch. Proc Natl Acad Sci USA. 1992,89(23): 11569-11573.
18. Ames JB, Ishima R, Tanaka T, Gordon JI, Stryer L, Ikura M. Molecular mechanics of calcium-myristoyl switches. Nature. 1997, 389(6647): 198-202.
19. O'Callaghan DW, Hasdemir B, Leighton M, Burgoyne RD. Residues within the myristoylation motif determine intracellular targeting of the neuronal Ca2+ sensor protein KChIP1 to post-ER transport vesicles and traffic of Kv4 K+ channels. J Cell Sci. 2003, 116(Pt 23):4833-4845.
20. O'Callaghan DW, Haynes LP, Burgoyne RD. High-affinity interaction of the N-terminal myristoylation motif of the neuronal calcium sensor protein hippocalcin with phosphatidylinositol 4,5-bisphosphate. Biochem J. 2005, 391 (Pt2):231-238.
21.Zhou W,Qian Y,Kunjilwar K,Pfaffinger PJ,Choe S.Structural insights into the functional interaction of KChIP1 with Shal-type K(+) channels.Neuron.2004,41(4):573-586.
22.Scannevin RH,Wang K,Jow F,Megules J,Kopsco DC,Edris W,Carroll KC,L(u|¨)Q,Xu W,Xu Z,Katz AH,Olland S,Lin L,Taylor M,Stahl M,Malakian K,Somers W,Mosyak L,Bowlby MR,Chanda P,Rhodes KJ.Two N-terminal domains of Kv4 K(+) channels regulate binding to and modulation by KChIP1.Neuron.2004,41(4):587-598.