CHROMOGRANIN A--NICOTINIC SIGNALING AND DESENSITIZATION
CHROMOGRANIN A--NICOTINIC SIGNALING AND DESENSITIZATION
批准号:
6378710
负责人:
SUSHIL K MAHATA
金额:
$8.99万
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-09-30 至 2003-08-31
中文摘要
嗜铬粒素A:烟碱信号和脱敏。尼古丁是一种
烟草的一种成分,尽管有害,但仍会刺激人们继续滥用
效果。儿茶酚胺能细胞的儿茶酚胺释放被触发
通过烟碱能胆碱能刺激,促使胞吐共释放
储存囊成分:儿茶酚胺、神经肽和酸性物质
嗜铬颗粒蛋白,主要成分为嗜铬颗粒蛋白A(CGA)。CGA
被切割成生物活性多肽,例如一个新的片段
(CgA344-364,我们发现并命名为儿茶素)
反馈-抑制儿茶酚胺的释放。我们发现,刺激
神经元尼古丁受体引起儿茶酚胺的分泌和
CGA,转录上调CGA和CGA的生物合成
儿茶酚胺,并进一步脱敏(产生耐受性)
尼古丁反应,包括分泌和转录。在预赛中
研究发现,儿茶素能拮抗所有这些胆碱能
回应。因此,CgA(及其片段儿茶素)似乎扮演着一个
在神经元型烟碱能胆碱能信号中的中心作用
对尼古丁呈阳性反应(在分泌和转录方面),以及
在阻断所有已知的刺激(分泌或转录)或
尼古丁的脱敏作用。CGA的这些特点和
儿茶素的反应和作用表明体内平衡是负面的
反馈作用。在这里,我们将探索CGA的这些功能和
儿茶素,使用培养的嗜铬细胞。以下是两个主要领域
特色化的。I.烟碱能胆碱能刺激引起的效应
(儿茶酚胺和CGA)分泌,CGA生物合成,以及
对进一步分泌或转录的脱敏(耐受性)
对尼古丁的反应。我们已经描述了CGA启动子的特征
调节尼古丁反应的结构域(在顺式中),并具有
开始建立信号转导通路,参与
转录及其脱敏。儿茶素的拮抗作用
烟碱反应(分泌、转录和脱敏
其一)。我们鉴定了儿茶素对分泌的抑制作用,
特别是作为非竞争性烟碱胆碱能拮抗剂,以及
确定了它对尼古丁信号转导的影响,以及
防止先前的烟碱脱敏。这些研究可能
建立一种新的动态平衡(负反馈)机制
一种内源性多肽拮抗烟碱刺激
儿茶酚胺释放、CGA基因转录和脱敏
包括分泌和转录。这种保护措施不会对
脱敏对机体来说可能是有利的
长期紧张的情况,也许是为了防范
提早终止分泌和转录反应
生理烟碱刺激。
英文摘要
Chromogranin A: nicotinic signaling and desensitization. Nicotine is a
component of tobacco that motivates continued abuse despite harmful
effects. Catecholamine release from catecholaminergic cells is triggered
by nicotinic cholinergic stimulation, prompting exocytotic co-release of
storage vesicle constituents: catecholamines, neuropeptides, and acidic
chromogranins, the major component being chromogranin A (CgA). CgA
is cleaved to biologically active peptides, such as a novel fragment
(CgA344-364, which we discovered and named "catestatin") that
feedback-inhibits catecholamine release. We found that stimulation of
neuronal nicotinic receptors causes secretion of catecholamines and
CgA, transcriptionally upregulates the biosynthesis of CgA and
catecholamines, and desensitizes (creates tolerance to) further
nicotinic responses, both secretory and transcriptional. In preliminary
studies, we found that catestatin antagonized all of these cholinergic
responses. Thus, CgA (and its fragment catestatin) seem to play a
central role in neuronal nicotinic cholinergic signaling, both in
responding positively to nicotine (in secretion and transcription), and
in blocking all known stimulatory (secretory or transcriptional) or
desensitizing action of nicotine. These features of CgA's and
catestatin's responses and action suggest a homeostatic, negative
feedback role. Here we will explore these functions of CgA and
catestatin, using cultured chromaffin cells. Two general areas will be
characterized. I. Effects of nicotinic cholinergic stimulation to cause
secretion (of catecholamines and CgA), CgA biosynthesis, and
desensitization of (tolerance to) further secretion or transcriptional
responses to nicotine. We have already characterized CgA promoter
domains (in cis) which mediate the response to nicotine, and have
begun to establish signal transduction pathways involved in
transcription and its desensitization. II. Catestatin's antagonism of
nicotinic responses (secretion, transcription, and desensitization
thereof). We characterized catestatin's inhibitory effects on secretion,
specifically as a non-competitive nicotinic cholinergic antagonist, and
established its effect on nicotinic signal transduction, as well as
protection against prior nicotinic desensitization. These studies may
establish a novel homeostatic (negative feedback) mechanism by which
an endogenous peptide antagonizes nicotinic stimulation of
catecholamine release, CgA gene transcription, and desensitization of
both secretion and transcription. Such protection against
desensitization may be advantageous to an organism during
circumstances of prolonged stress, perhaps guarding against
premature termination of secretory and transcriptional responses to
physiological nicotinic stimulation.
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Neuroendocrine cell type-specific and inducible expression of the secretogranin II gene: crucial role of cyclic adenosine monophosphate and serum response elements.
神经内分泌细胞类型特异性和分泌粒素 II 基因的诱导表达:环磷酸腺苷和血清反应元件的关键作用。
DOI:
10.1210/endo.140.2.6476
发表时间:
1999
期刊:
Endocrinology.
影响因子:
--
作者:
[Mahata,SK, Mahata,M, Livsey,CV, Gerdes,HH, Huttner,WB, O'Connor,DT]
通讯作者:
O'Connor,DT
Proadrenomedullin N-terminal 20 peptide: minimal active region to regulate nicotinic receptors.
肾上腺髓质素原 N 端 20 肽:调节烟碱受体的最小活性区域。
DOI:
10.1161/01.hyp.32.5.907
发表时间:
1998
期刊:
Hypertension (Dallas, Tex. : 1979)
影响因子:
--
作者:
[Mahata,M, Mahata,SK, Parmer,RJ, O'Connor,DT]
通讯作者:
O'Connor,DT
Neuroendocrine cell type-specific and inducible expression of the chromogranin B gene: crucial role of the proximal promoter.
神经内分泌细胞类型特异性和嗜铬粒蛋白 B 基因的诱导表达:近端启动子的关键作用。
DOI:
10.1210/endo.141.10.7725
发表时间:
2000
期刊:
Endocrinology.
影响因子:
--
作者:
[Mahapatra,NR, Mahata,M, Datta,AK, Gerdes,HH, Huttner,WB, O'Connor,DT, Mahata,SK]
通讯作者:
Mahata,SK
The novel catecholamine release-inhibitory peptide catestatin (chromogranin A344-364). Properties and function.
新型儿茶酚胺释放抑制肽儿茶素(嗜铬粒蛋白 A344-364)。
DOI:
10.1007/0-306-46837-9_21
发表时间:
2000
期刊:
Advances in experimental medicine and biology
影响因子:
--
作者:
[Mahata,SK, Mahata,M, LivseyTaylor,CV, Taupenot,L, Parmer,RJ, O'Connor,DT]
通讯作者:
O'Connor,DT
Secretin activation of chromogranin A gene transcription. Identification of the signaling pathways in cis and in trans.
促胰液素激活嗜铬粒蛋白 A 基因转录。
DOI:
10.1074/jbc.m207983200
发表时间:
2003
期刊:
The Journal of biological chemistry
影响因子:
--
作者:
[Mahapatra,NitishR, Mahata,Manjula, O'Connor,DanielT, Mahata,SushilK]
通讯作者:
Mahata,SushilK
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