Mammalian adenylate cyclases (ACs) are pseudoheterodimers with dissimilar hexahelical membrane-anchors, isoform-specifically conserved for more than half a billion years. We exchanged both membrane anchors of the AC isoform 2 by the quorum-sensing receptor from Vibrio harveyi, CqsS, which has a ligand, Cholera-Autoinducer-1 (CAI-1). In the chimera, AC activity was stimulated by Gsα, CAI-1 had no effect. Surprisingly, CAI-1 inhibited Gsα stimulation. We report that Gsα stimulation of human AC isoforms 2, 3, 5, and 9 expressed in Sf9 cells is inhibited by serum as is AC activity in membranes isolated from rat brain cortex. AC2 activation by forskolin or forskolin/Gsα was similarly inhibited. Obviously, serum contains as yet unidentified factors affecting AC activity. The data establish a linkage in ACs, in which the membrane anchors, as receptors, transduce extracellular signals to the cytosolic catalytic dimer. A mechanistic three state model of AC regulation is presented compatible with all known regulatory inputs into mammalian ACs. The data allow designating the membrane anchors of mammalian ACs as orphan receptors, and establish a new level of AC regulation.

中文翻译：

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Gsα刺激哺乳动物腺苷酸环化酶受到其六螺旋膜锚的调节。

哺乳动物腺苷酸环化酶（ACs）是具有不同六螺旋膜锚的假异二聚体，其异构体特异性保留了超过十亿年。我们通过哈维弧菌CqsS的群体感应受体交换了AC同工型2的两个膜锚，该受体具有配体霍乱自动诱导剂1（CAI-1）。在嵌合体中，AC活性被Gsα刺激，CAI-1没有作用。令人惊讶地，CAI-1抑制了Gsα刺激。我们报告说，Gsα刺激Sf9细胞中表达的人AC同工型2、3、5和9受到血清的抑制，以及从大鼠大脑皮层分离的膜中的AC活性。类似地抑制了毛喉素或毛喉素/Gsα对AC2的活化。显然，血清中含有尚未发现的影响AC活性的因素。数据在AC中建立了联系，其中膜锚定为受体，将细胞外信号转导至胞质催化二聚体。提出了一种AC调节的机械三态模型，该模型与哺乳动物AC的所有已知调节输入兼容。数据允许将哺乳动物AC的膜锚定为孤儿受体，并建立了新的AC调节水平。