INRS - Institut Armand-Frappier, Groupe de Recherche en Ingénierie des Peptides et en Pharmacothérapie (GRIPP), Université du Québec, Ville de Laval, QC, Canada; INRS - Institut Armand-Frappier, Laboratoire d'études moléculaires et pharmacologiques des peptides (LEMPP), Université du Québec, Ville de Laval, QC, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
Biochem Pharmacol. 2018 Aug;154:193-202. doi: 10.1016/j.bcp.2018.04.024. Epub 2018 Apr 25.
The pituitary adenylate cyclase-activating polypeptide (PACAP), which exists in two isoforms of 27 and 38 amino acids, can induce neuronal protection in vitro and in vivo following the activation of PAC1, a class B G protein-coupled receptor (GPCR). With its potent neuroprotective and anti-inflammatory effects, this peptide represents a promising avenue for the development of therapeutic strategies to potentially cure or at least slow the progression of neurodegenerative disorders. Beyond the canonical G protein signal effectors, GPCRs are also coupled to a multitude of intracellular signaling pathways that can be independently activated by biased ligands, thereby expanding vastly the potential for discovering new drugs. Interestingly, some studies have demonstrated distinct signaling features for the PACAP isoforms. With this observation in mind, we assessed the impact of chemical and structural modifications introduced into specific regions of the PACAP isoforms on their neuroprotective effects, and determined the role played by these physico-chemical and structural features on their signaling signatures. Each compound was also evaluated for its ability to bind the PACAP receptors, promote cell survival in a cellular model of Parkinson's disease and stimulate the signaling partners associated with PAC1 activation, including G and G, as well as β-arrestin 1 and 2. Our results demonstrate that PACAP38 and its related analogs exert a more potent neuroprotective action than their 27-amino acid counterparts and that this neuroprotective effect is dependent on both G and G-dependent signaling. This study will definitely improve our understanding of the molecular and cellular mechanisms associated with PACAP neuroprotection.
垂体腺苷酸环化酶激活肽（PACAP）有两种 27 个和 38 个氨基酸的同工型，在激活 B 类 G 蛋白偶联受体（GPCR）PAC1 后，可在体外和体内诱导神经元保护。这种肽具有强大的神经保护和抗炎作用，为开发治疗策略提供了有希望的途径，可能治愈或至少减缓神经退行性疾病的进展。除了经典的 G 蛋白信号效应物外，GPCR 还与多种细胞内信号通路偶联，这些信号通路可以被偏倚配体独立激活，从而极大地扩展了发现新药的潜力。有趣的是，一些研究表明 PACAP 同工型具有不同的信号特征。考虑到这一观察结果，我们评估了在 PACAP 同工型的特定区域引入的化学和结构修饰对其神经保护作用的影响，并确定了这些物理化学和结构特征对其信号特征的作用。还评估了每个化合物结合 PACAP 受体的能力、在帕金森病细胞模型中促进细胞存活的能力以及刺激与 PAC1 激活相关的信号伙伴的能力，包括 G 和 G，以及β-arrestin 1 和 2。我们的结果表明，PACAP38 及其相关类似物比其 27 个氨基酸类似物具有更强的神经保护作用，并且这种神经保护作用依赖于 G 和 G 依赖性信号。这项研究将肯定提高我们对与 PACAP 神经保护相关的分子和细胞机制的理解。
