School of Biological Sciences, University of Auckland, Auckland, New Zealand.
School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
Br J Pharmacol. 2022 Feb;179(3):435-453. doi: 10.1111/bph.15700. Epub 2021 Oct 31.
The pituitary adenylate cyclase-activating peptide (PACAP) family is of clinical interest for the treatment of migraine. These peptides activate three different PACAP-responsive class B G protein-coupled receptors: the PAC , VPAC and VPAC receptors. The PAC receptor may be alternatively spliced, generating variants that can differ in their pharmacological or signalling profiles. To inform drug discovery efforts targeting migraine, we need to better understand how the different PACAP-responsive receptors signal and how effectively these responses can be blocked by antagonists.
The signalling profiles of the human PAC , PAC , VPAC and VPAC receptors were examined in transfected Cos7 cells for cAMP, IP , pAkt, pERK and pCREB. Biased signalling was then quantified. The ability of antagonists to block PACAP-38, PACAP-27 or VIP stimulated cAMP accumulation at PACAP-responsive receptors was also determined.
PACAP-responsive receptors exhibited varied pharmacological profiles but activated signalling in a similar manner. The PAC and PAC receptors displayed distinct pharmacology. At the PAC receptor, VIP and PHM were more potent than at the PAC receptor. PACAP-responsive receptors displayed agonist-dependent antagonism where PACAP-38 was less effectively antagonised compared to PACAP-27 and VIP.
The distinct pharmacological profile displayed by the PAC receptor suggests that it can act as a dual receptor for VIP and PACAP. Furthermore, the effectiveness of blocking a signalling pathway can be influenced by which endogenous PACAP family agonist is present. These effects have potential implications for the development and effectiveness of drugs targeting the PACAP system.
This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.
垂体腺苷酸环化酶激活肽（PACAP）家族因其在偏头痛治疗方面的应用前景而备受关注。这些肽类可激活三种不同的 PACAP 反应性 B 类 G 蛋白偶联受体：PAC、VPAC 和 VPAC 受体。PAC 受体可能存在选择性剪接，产生在药理学或信号转导特征上存在差异的变体。为了为偏头痛的药物研发提供信息，我们需要更好地了解不同的 PACAP 反应性受体如何信号转导，以及拮抗剂能在多大程度上有效阻断这些反应。
在转染的 Cos7 细胞中，检测人 PAC、PAC、VPAC 和 VPAC 受体的信号转导谱，以检测 cAMP、IP、pAkt、pERK 和 pCREB。然后定量分析偏倚信号。还确定了拮抗剂阻断 PACAP-38、PACAP-27 或 VIP 刺激 PACAP 反应性受体时 cAMP 积累的能力。
PACAP 反应性受体表现出不同的药理学特征，但以相似的方式激活信号转导。PAC 和 PAC 受体表现出不同的药理学特性。在 PAC 受体上，VIP 和 PHM 的作用比 PAC 受体更有效。PACAP 反应性受体表现出激动剂依赖性拮抗作用，与 PACAP-27 和 VIP 相比，PACAP-38 的拮抗作用效果较差。
PAC 受体显示出独特的药理学特征，表明它可以作为 VIP 和 PACAP 的双重受体。此外，阻断信号通路的有效性可能会受到存在的内源性 PACAP 家族激动剂的影响。这些作用对靶向 PACAP 系统的药物的开发和有效性具有潜在影响。
本文是关于偏头痛和头痛治疗进展的专题（BJP 75 周年纪念）的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc。
