王 琪

華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院中西醫(yī)結(jié)合研究所,武漢 430030

縫隙連接蛋白(connexin,Cx)是構(gòu)成縫隙連接(gap junction,GJ)通道的基本結(jié)構(gòu)和功能蛋白,每6個(gè)跨膜的蛋白亞基圍繞中央孔(直徑1.5～2.0 nm)排列形成一個(gè)連接子(connexon)(即半通道,hemichannels),相鄰細(xì)胞膜上的連接子對(duì)接形成GJ[1]。在細(xì)胞間通道形成前,半通道呈關(guān)閉狀態(tài),而當(dāng)相鄰細(xì)胞的半通道連接時(shí),在細(xì)胞間形成直徑約1.5 nm的水性通道,細(xì)胞內(nèi)的離子和小分子物質(zhì)可借此出入相鄰細(xì)胞[2]。Cx廣泛存在于哺乳動(dòng)物各器官、組織中(紅細(xì)胞、骨骼肌除外),目前,在哺乳動(dòng)物中發(fā)現(xiàn)的連接蛋白至少有20種[3],分子質(zhì)量由26 kD～56 kD,據(jù)其基因序列的同源性程度及細(xì)胞質(zhì)內(nèi)環(huán)狀結(jié)構(gòu)域的長(zhǎng)度分為不同的亞類(lèi),如α-Cx族、β-Cx族和γ-Cx族[3]。Cx具有高度保守的氨基酸序列,每一個(gè)連接蛋白包含4個(gè)疏水性的跨膜區(qū),其氨基端和羧基端位于胞質(zhì)面,各成員間的差異主要在于胞質(zhì)面的2個(gè)環(huán)形結(jié)構(gòu)域及羧基端。不同Cx分子之間組合形成的縫隙連接通道的滲透性和導(dǎo)電性也有所不同[4]。Cx43是Cx基因家族中數(shù)量最為豐富的成員,迄今已發(fā)現(xiàn)存在于34種組織和46種細(xì)胞中[5],在GJ介導(dǎo)的縫隙連接通迅(gap junction intercelluar communication,GJIC)方面發(fā)揮著重要的作用,與創(chuàng)傷愈合、心血管病、腫瘤及神經(jīng)系統(tǒng)等多種疾病的發(fā)生密切相關(guān),是國(guó)內(nèi)外研究的熱點(diǎn)。

1 Cx43的結(jié)構(gòu)

Cx基因家族高度保守,不同的Cx具有共同的結(jié)構(gòu)特征。Cx43屬于α-Cx亞族,分子質(zhì)量43 kD,其肽鏈由382個(gè)氨基酸構(gòu)成,其中氨基酸1～242構(gòu)成管道部分,243～382為細(xì)胞質(zhì)尾部[6]。氨基末端(N端)至羧基末端(C端)共出入細(xì)胞膜4次,形成2個(gè)胞外環(huán)和1個(gè)胞內(nèi)環(huán),4個(gè)α螺旋結(jié)構(gòu)的跨膜片段。Cx最為保守的區(qū)域是2個(gè)胞外環(huán),其次是4個(gè)跨膜片段,N端保守性次于跨膜片段,但C端的氨基酸排列及數(shù)量在各個(gè)連接蛋白中差異明顯。Cx43的細(xì)胞質(zhì)尾部在不同種屬和不同組織間長(zhǎng)度稍有變化[7]。此外,Cx的大多數(shù)功能調(diào)節(jié)位點(diǎn)也在C端[8]。

2 Cx43基因的轉(zhuǎn)錄調(diào)節(jié)

2.1 轉(zhuǎn)錄因子調(diào)節(jié)

Cx43基因位于染色體 6q21～6q23.2,全長(zhǎng) 14 kb,由2個(gè)外顯子和1個(gè)內(nèi)含子組成。在Cx43的啟動(dòng)子區(qū)(-164～+148)分別存在1個(gè)AP1位點(diǎn)(-44～-36)和2個(gè)Sp1位點(diǎn)(-77～-69,-59～-48)。[9]AP1位點(diǎn)是c-Jun和c-Fos轉(zhuǎn)錄因子家族的同源結(jié)合區(qū)。c-Jun和c-Fos作為“即刻-早期”基因的產(chǎn)物可誘導(dǎo)具有AP1位點(diǎn)的“晚期”基因的表達(dá)。PKC活化后的級(jí)聯(lián)反應(yīng)可通過(guò)AP1位點(diǎn)上調(diào)Cx43的表達(dá)[9]。此外,Cx43的轉(zhuǎn)錄表達(dá)也受Wnt1信號(hào)途徑的激活[10]。

2.2 激素調(diào)節(jié)

雌激素可活化Cx43的啟動(dòng)子,并可通過(guò)上調(diào)c-Jun和c-Fos mRNA的表達(dá)而間接上調(diào)Cx43。此外,Cx43轉(zhuǎn)錄產(chǎn)物3'端非翻譯區(qū)與激素調(diào)節(jié)的產(chǎn)物穩(wěn)定性相關(guān)[9]。

2.3 甲基化影響

Chen等[11]通過(guò)檢測(cè)90例患者肺腫瘤組織及其鄰近正常組織的Cx43的表達(dá),發(fā)現(xiàn)33例Cx43表達(dá)陰性患者中,63.7%患者呈現(xiàn)Cx43基因啟動(dòng)子甲基化,而Cx43表達(dá)陽(yáng)性患者僅有5.3%表現(xiàn)甲基化,提示Cx43表達(dá)缺陷與甲基化有關(guān)。

3 Cx43的磷酸化調(diào)節(jié)

蛋白質(zhì)磷酸化作用是真核細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)中的核心,磷酸化可作為一個(gè)分子開(kāi)關(guān)在代謝、信號(hào)轉(zhuǎn)導(dǎo)和細(xì)胞分裂等方面控制蛋白質(zhì)的活性。Cx43的磷酸化與去磷酸化對(duì)GJ通道的功能有非常重要的影響[12]。Cx43的C端241～382為主要磷酸化區(qū),也是多種激素的識(shí)別位點(diǎn),絲氨酸、蘇氨酸及酪氨酸殘基的磷酸化程度決定著GJ通道的通透性及功能。Cx43羧基端的部分絲氨酸和蘇氨酸殘基在發(fā)生磷酸化后能夠影響 Cx43在細(xì)胞膜上的組裝、降解及 GJ介導(dǎo)的GJIC。研究發(fā)現(xiàn),多種蛋白激酶都可直接或間接磷酸化連接蛋白,從而影響GJIC功能。

3.1 蛋白激酶A(cAMP-dependent protein kinase,PKA)

PKA可與cAMP結(jié)合并被其激活。激活的PKA對(duì)GJIC功能有3種不同的影響,包括緩慢上調(diào)GJIC功能、快速下調(diào)GJIC功能和快速上調(diào)GJIC功能。PKA在體外能否直接磷酸化Cx43一直存有爭(zhēng)議。Bao等[13]發(fā)現(xiàn)PKA可使Cx43的Ser368位點(diǎn)發(fā)生磷酸化,從而改變Cx43的構(gòu)象,下調(diào)GJIC功能。Yogo等[14]發(fā)現(xiàn)卵泡刺激素可引起大鼠顆粒細(xì)胞Cx43的Ser365、Ser368 、Ser369、Ser373等位點(diǎn)的超磷酸化,并證明這些位點(diǎn)的磷酸化由PKA介導(dǎo)。但在部分細(xì)胞,如表達(dá)Cx43的胰腺癌細(xì)胞(PANC-1),PKA激活劑影響GJIC的功能只與Cx定位改變有關(guān),而與磷酸化狀態(tài)無(wú)關(guān)[15]。因此,PKA對(duì)Cx43的磷酸化作用還有待進(jìn)一步研究證實(shí)。

3.2 蛋白激酶C(protein kinase C,PKC)

PKC是一類(lèi)Ca2+、磷脂依賴(lài)性的蛋白激酶。體外的研究[13]表明,PKC可使 Cx43的 Ser368和Ser262位點(diǎn)發(fā)生磷酸化,其中,Ser368的磷酸化使Cx43蛋白的C-端肽鏈發(fā)生構(gòu)象改變,下調(diào)GJIC功能。PKC的激動(dòng)劑佛波醇乙酯可增強(qiáng)Ser262和Ser368的磷酸化程度,降低GJ功能[16]。Lin等[17]發(fā)現(xiàn)在鏈脲菌素誘導(dǎo)的糖尿病鼠的心肌細(xì)胞,PKC可介導(dǎo)Cx43發(fā)生過(guò)磷酸化,降低細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路的電傳導(dǎo)率。然而,在胎鼠的心肌細(xì)胞,使用佛波酯(12-O-tetradecanoylphorbol-13-acetate,TPA)作用后,細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路的電傳導(dǎo)率沒(méi)有降低或提高,但細(xì)胞的GJIC功能仍被抑制[18]。說(shuō)明在不同的細(xì)胞中,PKC對(duì)GJIC功能的調(diào)節(jié)機(jī)制可能有所不同。

3.3 蛋白激酶G(protein kinase G,PKG)

在大鼠心肌細(xì)胞中,環(huán)磷酸鳥(niǎo)苷可激活PKG,能通過(guò)磷酸化Cx43的Ser257位點(diǎn),降低單通道傳導(dǎo)性,使細(xì)胞間傳導(dǎo)性和對(duì)染料的通透性降低[19]。

3.4 絲裂原活化蛋白激酶(mitogen activated protein kinase,MAPK)

MAPK 家族包括 ERK1/2、ERK5、p38、JNK 等,是與細(xì)胞生長(zhǎng)、分化、凋亡等密切相關(guān)的信號(hào)轉(zhuǎn)導(dǎo)途徑中的關(guān)鍵物質(zhì),可由多種方式激活。如將甲萘醌作用于小鼠肝上皮細(xì)胞,可通過(guò)與EGF受體結(jié)合,進(jìn)而激活ERK,使Cx43的Ser279和Ser282位點(diǎn)發(fā)生磷酸化,下調(diào)GJIC功能[20]。壬基酚可通過(guò)p38-MAPK途徑使Cx43發(fā)生磷酸化,下調(diào)GJIC功能[21]。

3.5 酪蛋白激酶1(casein kinase,CK1)

CK1可直接磷酸化Cx43的 Ser325、Ser328或Ser330等位點(diǎn),調(diào)節(jié)細(xì)胞膜上的Cx43裝配;使用CK1的抑制劑后,胞內(nèi)Cx43的表達(dá)增多,胞膜上表達(dá)減少,同時(shí)Cx43的磷酸化減少[22]。

3.6 蛋白酪氨酸激酶(protein tyrosine kinase,PTK)

3.6.1 非受體型PTK 非受體酪氨酸激酶家族主要有9個(gè)亞族,研究較多的是Src家族。c-Src蛋白激酶是正常細(xì)胞的酪氨酸特異性蛋白激酶,其基因輕微改變后表達(dá)的v-Src蛋白激酶則是一種致瘤性蛋白激酶。Src通過(guò)多種機(jī)制影響Cx43通道功能:①作用于PKC、MAPK等磷酸化Cx43,抑制通道功能;②影響能作用于通道功能的蛋白質(zhì)的表達(dá);③直接磷酸化Cx43[23]。v-Src可直接磷酸化 Cx43的 Tyr247和Tyr265位點(diǎn)引起通道關(guān)閉,可能與降低通道開(kāi)放概率有關(guān),而非通過(guò)降低單通道傳導(dǎo)性[24]。

3.6.2 受體型PTK 根據(jù)結(jié)構(gòu)不同,受體型PTK可分為9種類(lèi)型,較常見(jiàn)的有4種:表皮生長(zhǎng)因子受體(EGFR)、家族胰島素受體家族、PDGF/MCSF/SCF受體家族及成纖維細(xì)胞生長(zhǎng)因子受體(FGFR)家族。如EGF可通過(guò)與EGFR結(jié)合活化PTK,使Cx43的Ser255、Ser279及Ser282位點(diǎn)發(fā)生磷酸化,下調(diào)GJIC功能[25]。

4 Cx43與相關(guān)疾病研究

4.1 Cx43與皮膚創(chuàng)傷

Cx43在創(chuàng)傷愈合過(guò)程中的細(xì)胞遷移、增生、炎癥反應(yīng)及收縮等方面發(fā)揮著重要的作用。作為皮膚、毛囊、汗腺、皮脂腺中的主要Cx之一,正常情況下,Cx43蛋白主要表達(dá)于表皮的基底層細(xì)胞、基底上的棘層細(xì)胞的胞膜上。創(chuàng)傷發(fā)生后,Cx43在創(chuàng)傷的邊緣表達(dá)降低,直到血凝塊下的表皮融合并開(kāi)始重新上皮化。Coutinho等[26]在中度燒傷早期的患者創(chuàng)面局部使用Cx43的反義寡核苷酸,發(fā)現(xiàn)可有效減少燒傷組織損傷加重的程度,而且創(chuàng)傷愈合過(guò)程中表皮增生加快、炎癥反應(yīng)降低、肉芽組織及瘢痕的形成減少。Mori等[27]同樣在燒傷早期的患者創(chuàng)面局部使用Cx43的反義寡核苷酸,可促進(jìn)細(xì)胞遷移、增生,減輕炎癥,使創(chuàng)面愈合加快。表明Cx43表達(dá)下調(diào)在創(chuàng)面愈合過(guò)程中的重要性。Wang等[28]發(fā)現(xiàn)鏈脲菌素誘導(dǎo)的糖尿病大鼠皮膚Cx43異常表達(dá),傷口愈合延遲,在傷口局部使用Cx43的反義寡核苷酸凝膠可防止Cx43的異常上調(diào),表皮再生速度明顯增快。

4.2 Cx43與心血管疾病

Cx43是哺乳動(dòng)物心室肌細(xì)胞間最主要的Cx,除竇房結(jié)、房室結(jié)組織和部分傳導(dǎo)系統(tǒng)外,其余心肌的GJ處均含有Cx43[29]。而在血管壁中,Cx43也是含量最豐富的,在調(diào)節(jié)血管收縮和舒張功能中起到重要的作用[30]。GJ通道數(shù)目的減少或分布紊亂,將導(dǎo)致傳導(dǎo)異常,引發(fā)心律失常。在房顫患者及動(dòng)物模型中,通常可觀(guān)察到Cx43的異常表達(dá)及定位[31]。Danik等[32]發(fā)現(xiàn)心肌細(xì)胞Cx43基因敲除的小鼠可發(fā)生復(fù)雜性的快速心律失常。Bruce等[33]認(rèn)為Cx43表達(dá)下調(diào)及GJ減少是心力衰竭、心律失常的關(guān)鍵因素,而緊密連接蛋白(zonula occludens-1,ZO-1)可通過(guò)與Cx43相互作用,下調(diào)Cx43,使心臟GJ重構(gòu),參與心力衰竭的發(fā)生。心肌缺血及心肌梗死后,心律失常是潛在的具有生命危險(xiǎn)的并發(fā)癥,而GJ重構(gòu)是心肌梗死后發(fā)生室性心律失常的重要基質(zhì),心肌梗死區(qū)尚存活但有變性的心肌細(xì)胞間的GJ發(fā)生重構(gòu),形成折返環(huán)路是形成室性心律失常的重要原因。Kanno等[34]發(fā)現(xiàn)Cx43的表達(dá)含量是心肌梗死面積大小的關(guān)鍵因素,通過(guò)增強(qiáng)細(xì)胞間傳導(dǎo)來(lái)降低心律失常發(fā)生的藥物可以增大心肌梗死的面積。Beardslee等[35]發(fā)現(xiàn)心肌組織隨缺血情況的加重可能導(dǎo)致磷酸化的Cx43水平下降而去磷酸化的Cx43水平升高,認(rèn)為Cx43的去磷酸化和細(xì)胞內(nèi)的ATP水解互為因果由此影響了細(xì)胞間電耦聯(lián),導(dǎo)致傳導(dǎo)異常和形成折返性心律失常。不過(guò),Formigli等[36]在豬左室負(fù)荷過(guò)重模型中發(fā)現(xiàn),心室舒張期容積增大引起的室壁張力增加和神經(jīng)體液因子的共同作用可能使Cx43增加,減少缺血/再灌注引發(fā)的細(xì)胞腫脹,促進(jìn)心肌細(xì)胞的分化,發(fā)揮心肌保護(hù)作用。此外,Cx43與動(dòng)脈粥樣硬化及高血壓亦有一定相關(guān)性[37-38]。

4.3 Cx43與腫瘤

GJIC異常與腫瘤的發(fā)生、發(fā)展關(guān)系密切。應(yīng)用Cx反義寡核苷酸技術(shù)、基因敲除及對(duì)Cx功能的顯性負(fù)抑制技術(shù)阻斷非腫瘤細(xì)胞GJIC,結(jié)果導(dǎo)致這些細(xì)胞失去對(duì)生長(zhǎng)的控制,極易形成腫瘤;另一方面,研究者[39]發(fā)現(xiàn)高轉(zhuǎn)移性腫瘤同型GJIC水平顯著低于低轉(zhuǎn)移性腫瘤,證實(shí)GJIC的變化與腫瘤的轉(zhuǎn)移相關(guān)。自殺基因治療是目前繼手術(shù)、化療和放療之后一種全新的腫瘤治療模式,該療法具有一種獨(dú)特的效應(yīng),稱(chēng)之為“旁觀(guān)者效應(yīng)”(by-stander effect,BE),即僅有部分腫瘤細(xì)胞轉(zhuǎn)染目的基因,在運(yùn)用前體藥物后可引起強(qiáng)大的殺瘤效應(yīng),包括被轉(zhuǎn)染細(xì)胞及周?chē)幢晦D(zhuǎn)染細(xì)胞均被殺滅,擴(kuò)大了自殺基因?qū)δ[瘤細(xì)胞的殺傷作用,而Cx介導(dǎo)的GJIC與BE關(guān)系密切[40],尤其以Cx43最為關(guān)鍵。Cx43是數(shù)量最為豐富的Cx,在多種腫瘤細(xì)胞中,均可見(jiàn)Cx43的表達(dá)降低甚至缺失[41];而上調(diào)Cx43表達(dá)可增強(qiáng)腫瘤細(xì)胞對(duì)化療藥物的敏感性[42-43]。Bier等[44]采用基因抑制(gene knockdown)的方法,發(fā)現(xiàn)在乳腺癌細(xì)胞中抑制Cx43假基因(Ψ Cx43),可促進(jìn)Cx43 RNA及蛋白的表達(dá),增強(qiáng)對(duì)化療藥物紫杉醇及多柔比星的敏感性。Cx43對(duì)腫瘤的抑制作用雖已為多數(shù)研究證實(shí),但機(jī)制尚未完全明確。Spinella等[45]發(fā)現(xiàn),內(nèi)皮素-1(endothelin-1,ET-1)可以自分泌的方式選擇性地作用于ETA受體,使卵巢癌細(xì)胞株出現(xiàn)約50%～75%的細(xì)胞間通訊減少及Cx43的表達(dá)下降。Langlois等[46]發(fā)現(xiàn)Caveolin與新合成的Cx43在高爾基體中相互作用形成復(fù)合體,分布在胞膜的脂筏中。經(jīng) tPA及EGF干預(yù)后的角質(zhì)化細(xì)胞,Caveolin-1與Cx43的結(jié)合減弱,認(rèn)為Caveolin-1在Cx43的抑瘤作用中具有一定作用[47]。

4.4 Cx43與神經(jīng)系統(tǒng)疾病

5 前景與展望

Cx43不僅與創(chuàng)傷愈合、心血管病、腫瘤、神經(jīng)系統(tǒng)等疾病的發(fā)生、發(fā)展過(guò)程密切相關(guān),而且與泌尿生殖系統(tǒng)、骨代謝及發(fā)育、白內(nèi)障等疾病的相關(guān)性研究也成為近期的研究熱點(diǎn)。但Cx43在相關(guān)疾病的發(fā)生、發(fā)展中的確切機(jī)制尚有待進(jìn)一步研究,如何開(kāi)發(fā)干預(yù)Cx43表達(dá),逆轉(zhuǎn)GJ的靶向藥物將是未來(lái)研究的新方向,為相關(guān)疾病的治療開(kāi)拓新的思路和途徑。此外,研究發(fā)現(xiàn)Cx43與經(jīng)絡(luò)有一定的相關(guān)性,將可能成為經(jīng)絡(luò)實(shí)質(zhì)研究的新方向。

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