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哺乳动物腺苷酸环化酶的膜结构域是脂质受体。

The membrane domains of mammalian adenylyl cyclases are lipid receptors.

机构信息

Pharmazeutisches Institut der Universität Tübingen, Tübingen, Germany.

Max-Planck-Institut für Biologie, Tübingen, Germany.

出版信息

Elife. 2024 Nov 29;13:RP101483. doi: 10.7554/eLife.101483.

DOI:10.7554/eLife.101483
PMID:39611663
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11606603/
Abstract

The biosynthesis of cyclic 3',5'-adenosine monophosphate (cAMP) by mammalian membrane-bound adenylyl cyclases (mACs) is predominantly regulated by G-protein-coupled receptors (GPCRs). Up to now the two hexahelical transmembrane domains of mACs were considered to fix the enzyme to membranes. Here, we show that the transmembrane domains serve in addition as signal receptors and transmitters of lipid signals that control Gsα-stimulated mAC activities. We identify aliphatic fatty acids and anandamide as receptor ligands of mAC isoforms 1-7 and 9. The ligands enhance (mAC isoforms 2, 3, 7, and 9) or attenuate (isoforms 1, 4, 5, and 6) Gsα-stimulated mAC activities in vitro and in vivo. Substitution of the stimulatory membrane receptor of mAC3 by the inhibitory receptor of mAC5 results in a ligand inhibited mAC5-mAC3 chimera. Thus, we discovered a new class of membrane receptors in which two signaling modalities are at a crossing, direct tonic lipid and indirect phasic GPCR-Gsα signaling regulating the biosynthesis of cAMP.

摘要

哺乳动物膜结合腺苷酸环化酶（mAC）中环 3'，5'-单磷酸腺苷（cAMP）的生物合成主要受 G 蛋白偶联受体（GPCR）调控。到目前为止，mAC 的两个六螺旋跨膜结构域被认为将酶固定在膜上。在这里，我们表明跨膜结构域除了作为信号受体之外，还作为脂质信号的传递体，控制 Gsα 刺激的 mAC 活性。我们鉴定出脂肪族脂肪酸和大麻素作为 mAC 同工型 1-7 和 9 的受体配体。这些配体增强（同工型 2、3、7 和 9）或减弱（同工型 1、4、5 和 6）体外和体内 Gsα 刺激的 mAC 活性。用 mAC5 的抑制性膜受体替代 mAC3 的刺激性膜受体，导致配体抑制的 mAC5-mAC3 嵌合体。因此，我们发现了一类新的膜受体，其中两种信号方式在交叉点，直接持续的脂质和间接的阶段性 GPCR-Gsα 信号调节 cAMP 的生物合成。

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