Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor.,ACS Chemical Neuroscience

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Membrane-Dependent Binding and Entry Mechanism of Dopamine into Its Receptor.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-06-15 , DOI: 10.1021/acschemneuro.9b00656
Fabio Lolicato _{1,

2} , Hanna Juhola ₃ , Agata Zak ₄ , Pekka A Postila ₅ , Annina Saukko _{6,

7} , Sami Rissanen ₃ , Giray Enkavi ₁ , Ilpo Vattulainen _{1,

3,

8} , Mariusz Kepczynski ₄ , Tomasz Róg ₁

Affiliation

Synaptic neurotransmission has recently been proposed to function via either a membrane-independent or a membrane-dependent mechanism, depending on the neurotransmitter type. In the membrane-dependent mechanism, amphipathic neurotransmitters first partition to the lipid headgroup region and then diffuse along the membrane plane to their membrane-buried receptors. However, to date, this mechanism has not been demonstrated for any neurotransmitter–receptor complex. Here, we combined isothermal calorimetry measurements with a diverse set of molecular dynamics simulation methods to investigate the partitioning of an amphipathic neurotransmitter (dopamine) and the mechanism of its entry into the ligand-binding site. Our results show that the binding of dopamine to its receptor is consistent with the membrane-dependent binding and entry mechanism. Both experimental and simulation results showed that dopamine favors binding to lipid membranes especially in the headgroup region. Moreover, our simulations revealed a ligand-entry pathway from the membrane to the binding site. This pathway passes through a lateral gate between transmembrane alpha-helices 5 and 6 on the membrane-facing side of the protein. All in all, our results demonstrate that dopamine binds to its receptor by a membrane-dependent mechanism, and this is complemented by the more traditional binding mechanism directly through the aqueous phase. The results suggest that the membrane-dependent mechanism is common in other synaptic receptors, too.

中文翻译：

多巴胺的膜依赖性结合和进入机制。

近年来，根据神经递质的类型，已提出突触神经传递通过膜独立或膜依赖机制起作用。在膜依赖性机制中，两亲性神经递质首先分配至脂质头基区域，然后沿膜平面扩散至其膜埋入受体。但是，迄今为止，尚未针对任何神经递质-受体复合物证明这种机制。在这里，我们将等温量热法测量与多种分子动力学模拟方法相结合，以研究两亲性神经递质（多巴胺）的分配及其进入配体结合位点的机制。我们的结果表明，多巴胺与其受体的结合与膜依赖性结合和进入机制一致。实验和模拟结果均表明，多巴胺有利于结合脂质膜，尤其是在头基区域。此外，我们的模拟揭示了从膜到结合位点的配体进入途径。该途径穿过跨膜α-螺旋5和6之间的横向门，该跨膜在蛋白的面向膜侧。总而言之，我们的结果表明，多巴胺通过膜依赖性机制与其受体结合，而这直接通过水相被更传统的结合机制所补充。结果表明，膜依赖性机制在其他突触受体中也很常见。我们的模拟揭示了从膜到结合位点的配体进入途径。该途径穿过蛋白膜表面一侧跨膜α-螺旋5和6之间的侧向门。总而言之，我们的结果表明，多巴胺通过膜依赖性机制与其受体结合，而这直接通过水相被更传统的结合机制所补充。结果表明，膜依赖性机制在其他突触受体中也很常见。我们的模拟揭示了从膜到结合位点的配体进入途径。该途径穿过蛋白膜表面一侧跨膜α-螺旋5和6之间的侧向门。总而言之，我们的结果表明，多巴胺通过膜依赖性机制与其受体结合，而这直接通过水相被更传统的结合机制所补充。结果表明，膜依赖性机制在其他突触受体中也很常见。并通过直接通过水相的更传统的结合机理加以补充。结果表明，膜依赖性机制在其他突触受体中也很常见。并通过直接通过水相的更传统的结合机理加以补充。结果表明，膜依赖性机制在其他突触受体中也很常见。

更新日期：2020-07-01

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