Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases.
Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases.
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DOI：
10.1016/j.pharmthera.2010.12.005
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发表时间：
2011-04
影响因子：
13.5
通讯作者：
Potter LR
中科院分区：
文献类型：
--
作者：
Potter LR
环GMP是一种普遍存在的第二信使，调节广泛的生理过程，如血压，长骨生长，肠液分泌，光转导和脂解。可溶性和单跨膜酶称为鸟苷酸环化酶（GC）合成cGMP。在人类中，后一组由GC-A、GC-B、GC-C、GC-E和GC-F组成，它们也分别被称为NPR-A、NPR-B、星星、Ret 1-GC和Ret 2-GC。膜GC被肽配体激活，所述肽配体例如心房利钠肽（ANP）、B型利钠肽（BNP）、C型利钠肽（CNP）、鸟苷素、尿鸟苷素、热稳定肠毒素和GC活化蛋白。奈西立肽和卡培立肽是临床批准的基于肽的药物，可激活GC-A。CD-NP是一种实验性心力衰竭药物，主要激活GC-B，但也在高浓度下激活GC-A，并且对降解具有抗性。GC-B中的失活突变导致肢端中肢发育不良型Maroteaux侏儒症，而增加CNP浓度的染色体突变与马法诺样骨骼过度生长相关。基于泵的CNP输注增加了最常见类型的人类侏儒症小鼠模型中的骨骼生长，这支持了基于CNP/GC-B的矮小症治疗。利那洛肽是一种GC-C肽激活剂，可刺激肠道运动，目前正处于治疗慢性便秘的后期临床试验阶段。本文综述了cGMP、鸟苷酸环化酶的发现、GC-A、GC-B和GC-C的一般特性及其在治疗中的应用，并着重介绍了磷酸化和ATP对跨膜鸟苷酸环化酶的调控。
Cyclic GMP is a ubiquitous second messenger that regulates a wide array of physiologic processes such as blood pressure, long bone growth, intestinal fluid secretion, phototransduction and lipolysis. Soluble and single-membrane-spanning enzymes called guanylyl cyclases (GC) synthesize cGMP. In humans, the latter group consists of GC-A, GC-B, GC-C, GC-E and GC-F, which are also known as NPR-A, NPR-B, StaR, Ret1-GC and Ret2-GC, respectively. Membrane GCs are activated by peptide ligands such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), guanylin, uroguanylin, heat stable enterotoxin and GC-activating proteins. Nesiritide and carperitide are clinically approved peptide-based drugs that activate GC-A. CD-NP is an experimental heart failure drug that primarily activates GC-B but also activates GC-A at high concentrations and is resistant to degradation. Inactivating mutations in GC-B cause acromesomelic dysplasia type Maroteaux dwarfism and chromosomal mutations that increase CNP concentrations are associated with Marfanoid-like skeletal overgrowth. Pump-based CNP infusions increase skeletal growth in a mouse model of the most common type of human dwarfism, which supports CNP/GC-B-based therapies for short stature diseases. Linaclotide is a peptide activator of GC-C that stimulates intestinal motility and is in late-stage clinical trials for the treatment of chronic constipation. This review discusses the discovery of cGMP, guanylyl cyclases, the general characteristics and therapeutic applications of GC-A, GC-B and GC-C, and emphasizes the regulation of transmembrane guanylyl cyclases by phosphorylation and ATP.