Duda Teresa, Pertzev Alexandre, Sharma Rameshwar K
The Unit of Regulatory and Molecular Biology, Research Divisions of Biochemistry and Molecular Biology, Salus University Elkins Park, PA, USA.
Front Mol Neurosci. 2014 Mar 17;7:17. doi: 10.3389/fnmol.2014.00017. eCollection 2014.
Atrial natriuretic factor receptor guanylate cyclase (ANF-RGC), was the first discovered member of the mammalian membrane guanylate cyclase family. The hallmark feature of the family is that a single protein contains both the site for recognition of the regulatory signal and the ability to transduce it into the production of the second messenger, cyclic GMP. For over two decades, the family has been classified into two subfamilies, the hormone receptor subfamily with ANF-RGC being its paramount member, and the Ca(2+) modulated subfamily, which includes the rod outer segment guanylate cyclases, ROS-GC1 and 2, and the olfactory neuroepithelial guanylate cyclase. ANF-RGC is the receptor and the signal transducer of the most hypotensive hormones, ANF- and B-type natriuretic peptide (BNP). After binding these hormones at the extracellular domain it, at its intracellular domain, signals activation of the C-terminal catalytic module and accelerates the production of cyclic GMP. Cyclic GMP then serves the second messenger role in biological responses of ANF and BNP such as natriuresis, diuresis, vasorelaxation, and anti-proliferation. Very recently another modus operandus for ANF-RGC was revealed. Its crux is that ANF-RGC activity is also regulated by Ca(2+). The Ca(2+) sensor neurocalcin d mediates this signaling mechanism. Strikingly, the Ca(2+) and ANF signaling mechanisms employ separate structural motifs of ANF-RGC in modulating its core catalytic domain in accelerating the production of cyclic GMP. In this review the biochemistry and physiology of these mechanisms with emphasis on cardiovascular regulation will be discussed.
心房利钠因子受体鸟苷酸环化酶（ANF-RGC）是哺乳动物膜鸟苷酸环化酶家族中首个被发现的成员。该家族的标志性特征是单个蛋白质既包含调节信号识别位点，又具备将其转化为第二信使环磷酸鸟苷（cGMP）生成的能力。二十多年来，该家族被分为两个亚家族，以ANF-RGC为主要成员的激素受体亚家族，以及包括视杆外段鸟苷酸环化酶ROS-GC1和ROS-GC2以及嗅觉神经上皮鸟苷酸环化酶的Ca(2+)调节亚家族。ANF-RGC是最具降压作用的激素心房利钠因子（ANF）和B型利钠肽（BNP）的受体及信号转导器。在细胞外结构域与这些激素结合后，它在细胞内结构域发出信号，激活C末端催化模块并加速cGMP的生成。然后，cGMP在ANF和BNP的生物反应如利钠、利尿、血管舒张和抗增殖中发挥第二信使作用。最近，ANF-RGC的另一种作用方式被揭示。其关键在于ANF-RGC的活性也受Ca(2+)调节。Ca(2+)传感器神经钙蛋白d介导这种信号传导机制。引人注目的是，Ca(2+)和ANF信号传导机制在调节其核心催化结构域以加速cGMP生成时采用ANF-RGC的不同结构基序。在这篇综述中，将讨论这些机制的生物化学和生理学，重点是心血管调节。
