β-Adrenergic activation of electrogenic K+ and Cl- secretion in guinea pig distal colonic epithelium proceeds via separate cAMP signaling pathways
β-Adrenergic activation of electrogenic K+ and Cl- secretion in guinea pig distal colonic epithelium proceeds via separate cAMP signaling pathways
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DOI：
10.1152/ajpgi.00035.2010
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发表时间：
2010-07-01
影响因子：
4.5
通讯作者：
Halm, Dan R.
中科院分区：
文献类型：
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作者：
Halm, Susan T.;Zhang, Jin;Halm, Dan R.
Halm ST，Zhang J，Halm DR.豚鼠远端结肠上皮细胞中的β-肾上腺素能激活通过单独的cAMP信号传导途径进行电性K+和Cl-分泌。美国生理学杂志胃肠和肝脏生理学299：G81-G95，2010年。首次发表于2010年4月22日; doi：10.1152/ajpgi.00035.2010。肾上腺素能刺激离体豚鼠远端结肠粘膜产生短暂的Cl-和持续的K+分泌。瞬时短路电流（I-sc）依赖于β（2）-肾上腺素能受体（β（2）-AdrR），持续I-sc依赖于β（1）-AdrR/β（2）-AdrR复合物。肾上腺素（epi）增加cAMP含量的双相时间过程类似于epi激活的I-sc（I-epi（sc））的变化。抑制跨膜腺苷酸环化酶（tmAC）可将峰值I-epi（sc）和cAMP降低至接近零，而不会降低持续I-epi（sc），这与来自仅用于Cl-分泌的tmAC信号传导的cAMP一致。抑制可溶性腺苷酸环化酶（sAC）可将持续的I-epi（sc）和cAMP降低至接近零，而不降低峰值I-epi（sc）或cAMP，这与来自sAC的cAMP信号传导K+分泌一致。对磷酸二酯酶（PDE）抑制剂和肽YY（PYY）刺激的敏感性进一步支持两种组分的单独信号传导。PDE 3或PDE 4抑制剂增强峰值I-epi（sc），但不维持I-epi（sc），这与作为β（2）-AdrR信号传导结构域一部分的这些PDE一致。PYY以百日咳毒素（PTx）敏感的方式抑制峰值I-epi（sc），支持产生cAMP用于Cl-分泌的tmAC的G α（i）依赖性抑制。由于PYY或PTx不改变持续的I-epi（sc），因此K+分泌的信号传导通过G alpha（i）-非依赖性机制发生。结构域特异性抗体支持结肠上皮细胞中存在多种sAC变体。对特异性激活剂和抑制剂的反应表明，蛋白激酶A不参与激活峰或持续组分的I-epi（SC），但cAMP依赖性鸟嘌呤核苷酸交换因子，Epac，可能作出贡献。因此，β-肾上腺素能激活产电Cl-和K+分泌，分别需要tmAC和sAC依赖性信号通路。
Halm ST, Zhang J, Halm DR. beta-Adrenergic activation of electrogenic K+ and Cl- secretion in guinea pig distal colonic epithelium proceeds via separate cAMP signaling pathways. Am J Physiol Gastrointest Liver Physiol 299: G81-G95, 2010. First published April 22, 2010; doi:10.1152/ajpgi.00035.2010.-Adrenergic stimulation of isolated guinea pig distal colonic mucosa produced transient Cl- and sustained K+ secretion. Transient short-circuit current (I-sc) depended on beta(2)-adrenergic receptors (beta(2)-AdrR), and sustained I-sc relies on a beta(1)-AdrR/beta(2)-AdrR complex. Epinephrine (epi) increased cAMP content with a biphasic time course similar to changes in epi-activated I-sc (I-epi(sc)). Inhibition of transmembrane adenylyl cyclases (tmACs) reduced peak I-epi(sc) and cAMP to near zero without decreasing sustained I-epi(sc), consistent with cAMP from tmAC signaling for only Cl- secretion. Inhibition of soluble adenylyl cyclase (sAC) reduced sustained I-epi(sc) and cAMP to near zero without decreasing peak I-epi(sc) or cAMP, consistent with cAMP from sAC signaling for K+ secretion. Sensitivity to phosphodiesterase (PDE) inhibitors and peptide YY (PYY) stimulation further supported separate signaling for the two components. PDE3 or PDE4 inhibitors enhanced peak I-epi(sc) but not sustained I-epi(sc), consistent with these PDEs as part of the beta(2)-AdrR signaling domain. PYY suppressed peak I-epi(sc) in a pertussis toxin (PTx)-sensitive manner, supporting G alpha(i)-dependent inhibition of tmACs producing cAMP for Cl- secretion. Since PYY or PTx did not alter sustained I-epi(sc), signaling for K+ secretion occurred via a G alpha(i)-independent mechanism. Presence of multiple sAC variants in colonic epithelial cells was supported by domain-specific antibodies. Responses to specific activators and inhibitors suggested that protein kinase A was not involved in activating peak or sustained components of I-epi(sc), but the cAMP-dependent guanine nucleotide exchange factor, Epac, may contribute. Thus beta-adrenergic activation of electrogenic Cl- and K+ secretion, respectively, required tmAC- and sAC-dependent signaling pathways.