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)域的長度分為不同的亞類,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 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活化后的級聯(lián)反應(yīng)可通過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]通過檢測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)胞信號轉(zhuǎn)導(dǎo)中的核心,磷酸化可作為一個(gè)分子開關(guān)在代謝、信號轉(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)無關(guān)[15]。因此,PKA對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Ca2+、磷脂依賴性的蛋白激酶。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)生過磷酸化,降低細(xì)胞信號轉(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)胞信號轉(zhuǎn)導(dǎo)通路的電傳導(dǎo)率沒有降低或提高,但細(xì)胞的GJIC功能仍被抑制[18]。說明在不同的細(xì)胞中,PKC對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)磷酸鳥苷可激活PKG,能通過磷酸化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、分化、凋亡等密切相關(guān)的信號轉(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,可能與降低通道開放概率有關(guān),而非通過降低單通道傳導(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種類型,較常見的有4種:表皮生長因子受體(EGFR)、家族胰島素受體家族、PDGF/MCSF/SCF受體家族及成纖維細(xì)胞生長因子受體(FGFR)家族。如EGF可通過與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?？捎^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,通過增強(qiáng)細(xì)胞間傳導(dǎo)來降低心律失常發(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,Formigli等[36]在豬左室負(fù)荷過重模型中發(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)胞失去對生長的控制,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),稱之為“旁觀者效應(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)胞及周圍未被轉(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)對化療藥物紫杉醇及多柔比星的敏感性。Cx43對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,如何開發(fā)干預(yù)Cx43表達(dá),逆轉(zhuǎn)GJ的靶向藥物將是未來研究的新方向,為相關(guān)疾病的治療開拓新的思路和途徑。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。

[1] WILLECKE K,EIBCRGER J,DEGEN J,et al.Structural and functional diversity of connexin genes in the mouse and human genome[J].Biol Chem,2002,383(5):725-737.

[2] SOHL G,WILLECKE K.Gap junctions and the connexin protein family[J].Cardiovasc Res,2004,62(2):228-232.

[3] LIAO Y,DAY KH,DAM ON DN,et al Endothelial cellspecific knockout of connexin 43 causes hypotention brady cardiain mice[J].Proc Natl Acad Sci USA,2001,98(17):9989-9994.

[4] HUANG XD,SANDUSKY GE,ZIPES DP.Heterogeneous loss of Cx43 protein in ischemic dog heats[J].J Cardiovasc Eletrophysiol,1999,10(1):79-91.

[5] LAIRD DW.Life cycle of connexins in health and disease[J].Biochem J,2006,394(Pt 3):527-543.

[6] YANCEY SB,JOHN SA,LAL R,et al.The 43-kD polypeptide of heart gap junctions:immunolocalization,topology,and functional domains[J].J Cell Biol,1989,108(6):2241-2254.

[7] BEYER EC,KISTLER J,PAUL DL,et al.Antisera directed against connexin43 peptides react with a 43-kD protein localized to gap junctions in myocardium and other tissues[J].J Cell Biol,1989,108(2):595-605.

[8] GOODENOUGH DA,GOLIGER JA,PAUL DL.Connexins,connexons,and intercellular communication[J].Annu Rev Biochem,1996,65:475-502.

[9] 徐婭蓓,陳國強(qiáng).間隙連接蛋白-43的表達(dá)調(diào)控及其功能[J].國際病理科學(xué)與臨床雜志,2005,25(6):477-480.

[10] van der HEYDEN MA,ROOK MB,HERMANS MM,et al.Identification of connexin43 as a functional target for Wnt signalling[J].J Cell Sci,1998,111(12):1741-1749.

[11] CHEN JT,CHENG YW,CHOU MC,et al.The correlation between aberrant connexin 43 mRNA expression induced by promoter methylation and nodal micrometastasis in non-small cell lung cancer[J].Clin Cancer Res,2003,9(11):4200-4204.

[12] LAMPE PD,LAU AF.Regulation of gap junctions by phosphorylation of connexins[J].Arch Biochem Biophys,2000,384(2):205-215.

[13] BAO X,REUSS L,ALTENBERG GA.Regulation of purified and reconstituted connexin 43 hemichannels by protein kinase C-mediated phosphorylation of Serine 368[J].J Biol Chem,2004,279(19):20058-20066.

[14] YOGO K,OGAWA T,AKIYAMA M,et al.PKA implicated in the phosphorylation of Cx43 induced by stimulation with FSH in rat granulosa cells[J].J Reprod Dev,2006,52(3):321-328.

[15] KAWASAKI Y,TSUCHIDA A,SASAKI T,et al.Irsogladinemalate up-regulates gap junctional intercellular communication between pancreatic cancer cells via PKA pathway[J].Pancreas,2002,25(4):373-377.

[16] SOLAN JL,LAM PE.Connexin phosphorylation as a regulatory event linked to gap junction channel assembly[J].Biochim Biophys Acta,2005,1711(2):154-163.

[17] LIN H,OGAWA K,IMANAGA I,et al.Alterations of connexin 43 in the diabetic rat heart[J].Adv Cardiol,2006,42:243-254.

[18] COT TRELL GT,LIN R,WA RN-CRAMER BJ,et al.Mechanism of v-Src and mitogen-activated protein kinaseinduced reduction of gap junction communication[J].Am J Physiol Cell Physiol,2003,284(2):511-520.

[19] GIEPM ANS BN.Gap junctions and connexin-interacting proteins[J].Cardiovasc Res,2004,62(2):233-245.

[20] ABDELMOHSEN K,von MONTFORT C,STUHLMANN D,et al.Doxorubicin induces EGF receptor-dependent downregulation of gap junctional intercellular communication in rat liver epithelial cells[J].Biol Chem,2005,386(3):217-223.

[21] ARAVINDAKSHAN J,CYRD G.Nonylphenol alters connexin 43 levels and connexin 43 phosphorylation via an inhibition of the p38-mitogen-activated protein kinase pathway[J].Biol Reprod,2005,72(5):1232-1240.

[22] COOPER CD,LAMPE PD.Casein kinase 1 regulates connexin43 gap junction assembly[J].J Biol Chem,2002,277(47):44962-44968.

[23] PAHUJAA M,ANIKIN M,GOLDBERG GS.Phosphorylation of connexin43 induced by Src:regulation of gap junctional communication between transformed cells[J].Exp Cell Res,2007,313(20):4083-4090.

[24] KWAK BR,van VEEN TA,ANALBERS LJ,et al.TPA increases conductance but decreases permeability in neonatal rat cardiomyocyte gap junction channels[J].Exp Cell Res,1995,220(2):456-463.

[25]CAMERON SJ,MALIK S,AKAIKE M,et al.Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation[J].Biol Chem,2003,278(20):18682-18688.

[26] COUTINHO P,QIU C,FRANK S,et al.Limiting burn extension bytransient inhibition of Connexin43 expression at the site of injury[J].Br J Plast Surg,2005,58(5):658-667.

[27] MORI R,POWER KT,WANG CM,et al.Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response,enhanced keratinocyte proliferation and wound fibroblast migration[J].J Cell Sci,2006,119(24):5193-5203.

[28] WANG CM,LINCOLN J,COOK JE,et al.Abnormal connexin expression underlies delayed wound healing in diabetic skin[J].Diabetes,2007,56(11):2809-2817.

[29] GROS DB,JONGSMA HJ.Connexins in mammalian heart function[J].Bioessays,1996,18(9):719-730.

[30] ISAKSON BE,DULING BR.Heterocellular Contact at the Myoendothelial junction influences gap junction organization[J].Circ Res,2005,97(1):44-51.

[31] DUFFY HS,WIT AL.Is there a role for remodeled connexins in AF?No simple answers[J].J Mol Cell Cardiol,2008,44(1):4-13.

[32] DANIK SB,ROSNER G,LADER J,et al.Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts[J].FASEB J,2008,22(4):1204-1212.

[33] BRUCE AF,ROTHERY S,DUPONT E,et al.Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1[J].Cardiovasc Res,2008,77(4):757-765.

[34] KANNO S,KOVACS A,YAMADA KA,et al.Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice[J].J Am Coll Cardiol,2003,41(4):681-686.

[35] BEARDSLEE MA,LERNER DL,TADROS PN,et al.D-ephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia[J].Circ Res,2000,87(8):656-662.

[36] FORMIGLI L,IBBA-MANNESCHI L,PERNA AM,et al.Altered Cx43 expression during myocardial adaptation to acute and chronic volume overloading[J].Histol Histopathol,2003,18(2):359-369.

[37] ISAKSON BE,KRONKE G,KADL A,et al.Oxidized phospholipids alter vascular connexin expression,phosphorylation,and heterocellular communication[J].Arterioscler Thromb Vasc Biol,2006,26(10):2216-2221.

[38] YEH HI,LEE PY,SU CH,et al.Reduced expression of endothelial connexins 43 and 37 in hypertensive rats is rectified after 7-day carvedilol treatment[J].Am J Hypertens,2006,19(2):129-135.

[39] SULKOWSKI S,SULKOWSKA M,SKRZYDLEWSKA E.Gap junctional intercellular communication and carcinogenesis[J].Pol J Pathol,1999,50(4):227-233.

[40] KAWAMURA K,BAHAR R,NAMBA H,et al.Bystander effect in uracil phosphoribosy-ltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intercellular communication[J].Int J Oncol,2001,18(1):117-120.

[41] NAUS CC.Gap junctions and tumour progression[J].C-an J Physiol Pharmacol,2002,80(2):136-141.

[42] HUANG RP,HOSSAIN MZ,HUANG R,et al.Connexin 43(cx43)enhances chemotherapy-induced apoptosis in human glioblastoma cells[J].Int J Cancer,2001,92(1):130-138.

[43] CARYSTINOS GD,ALAOUI-JAMALI MA,PHIPPS J,et al.Up-regulation of gap junctionalintercellular communication and connexin 43 expression by cyclic-AM P and all-trans-retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells[J].Cancer Chemother Pharmacol,2001,47(2):126-132.

[44] BIER A,OVIEDO-LANDAVERDE I,ZHAO J,et al.C-onnexin43 pseudogene in breast cancer cells offers a novel therapeutic target[J].Mol Cancer Ther,2009,8(4):786-793.

[45] SPINELLA F,ROSANO L,di CAST RTO V,et al.Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells[J].J Biol Chem,2003,278(42):41294-41301.

[46] LANGLOIS S,COWAN KN,SHAO Q,et al.Caveolin-1 and-2 interact with connexin43 and regulate gap junctional intercellular communication in keratinocytes[J].Mol Biol Cell,2008,19(3):912-928.

[47] LANGLOIS S,COWAN KN,SHAO Q,et al.The tumorsuppressive function of Connexin43 in keratinocytes is mediated in part via interaction with caveolin-1[J].Cancer Res,2010,70(10):4222-4232.

[48] FONSECA CG,GREEN CR,NICHOLSON LF.Upregulation in astrocytic connexin 43 gap junction levels may exacerbate generalized seizures in mesial temporal lobe epilepsy[J].Brain Res,2002,929(1):105-116.

[49] WANG HT,HONG T.Altered Expression of Connexin43 and Its Possible Role in Endothelin-1 induced Contraction in Rabbit Basilar Artery[J].Neurol Res,2009,31(1):67-73.

[50] CHANSON M,KOTSIAS BA,PERACCHIA C,et al.Interactions of connexins with other membrane channels and transporters[J].Prog Biophys M ol Biol,2007,94(1-2):233-244.

[51]吳中亮,廖春華,任寧.縫隙連接蛋白43與創(chuàng)傷后腦水腫相關(guān)性研究[J].中華神經(jīng)外科疾病研究雜志,2008,7(3):201-204.