Matt Rachel A, Westhorpe Frederick G, Romuar Rosemary F, Rana Payal, Gever Joel R, Ford Anthony P
Department of Pharmacology, CuraSen Therapeutics, San Carlos, CA, United States.
Front Mol Biosci. 2023 Aug 17;10:1214102. doi: 10.3389/fmolb.2023.1214102. eCollection 2023.
Noradrenergic projections from the brainstem locus coeruleus drive arousal, attentiveness, mood, and memory, but specific adrenoceptor (AR) function across the varied brain cell types has not been extensively characterized, especially with agonists. This study reports a pharmacological analysis of brain AR function, offering insights for innovative therapeutic interventions that might serve to compensate for locus coeruleus decline, known to develop in the earliest phases of neurodegenerative diseases. First, β-AR agonist activities were measured in recombinant cell systems and compared with those of isoprenaline to generate Δlog(E/EC) values, system-independent metrics of agonist activity, that, in turn, provide receptor subtype fingerprints. These fingerprints were then used to assess receptor subtype expression across human brain cell systems and compared with Δlog(E/EC) values arising from β-arrestin activation or measurements of cAMP response desensitization to assess the possibility of ligand bias among β-AR agonists. Agonist activity profiles were confirmed to be system-independent and, in particular, revealed β-AR functional expression across several human brain cell types. Broad β-AR function observed is consistent with noradrenergic tone arising from the locus coeruleus exerting heterocellular neuroexcitatory and homeostatic influence. Notably, Δlog(E/EC) measurements suggest that tested β-AR agonists do not show ligand bias as it pertains to homologous receptor desensitization in the system examined. Δlog(E/EC) agonist fingerprinting is a powerful means of assessing receptor subtype expression regardless of receptor expression levels or assay readout, and the method may be applicable to future use for novel ligands and tissues expressing any receptor with available reference agonists.
来自脑干蓝斑核的去甲肾上腺素能投射驱动觉醒、注意力、情绪和记忆，但不同脑细胞类型中特定肾上腺素能受体（AR）的功能尚未得到广泛表征，尤其是使用激动剂时。本研究报告了对脑AR功能的药理学分析，为创新治疗干预提供了见解，这些干预可能有助于补偿已知在神经退行性疾病最早阶段出现的蓝斑核衰退。首先，在重组细胞系统中测量β-AR激动剂活性，并与异丙肾上腺素的活性进行比较，以生成Δlog（E/EC）值，这是激动剂活性的系统无关指标，进而提供受体亚型指纹图谱。然后，这些指纹图谱用于评估人脑细胞系统中受体亚型的表达，并与β-抑制蛋白激活产生的Δlog（E/EC）值或cAMP反应脱敏测量值进行比较，以评估β-AR激动剂之间配体偏向的可能性。激动剂活性谱被证实是系统无关的，特别是揭示了几种人脑细胞类型中β-AR的功能表达。观察到的广泛β-AR功能与蓝斑核产生的去甲肾上腺素能张力发挥异细胞神经兴奋性和稳态影响一致。值得注意的是，Δlog（E/EC）测量表明，在所研究的系统中，测试的β-AR激动剂在同源受体脱敏方面没有显示出配体偏向。Δlog（E/EC）激动剂指纹图谱是一种评估受体亚型表达的有力手段，无论受体表达水平或检测读数如何，该方法可能适用于未来用于新型配体和表达任何具有可用参考激动剂的受体的组织。
