Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a

Stroke is among the top five leading causes of mortality globally. More than 80% of stroke cases result from ischemic stroke, leading to severe metabolic changes and neural cell death. One of the issues with stroke is that there is an urgent need to revive the blood flow to various brain areas. However, even after reestablishing blood flow, specific pathological chain reactions are challenging to reverse.

Studies show that many such chain reactions causing neural cell death occur secondary to prolonged acidosis. Researchers know some of the changes caused by this acidosis. And they also know that breaking the chain of these reactions post-stroke may considerably lower the rate of brain cell death and help reduce stroke-associated mortality. Further, it appears that one way to break these chain reactions is blocking the hyperactivity of so-called Acid-sensing ion channels (ASICs) in the brain.

ASICs are highly expressed especially in some brain regions like the hippocampus and amygdala. These channels play a vital role in learning and memory. However, dysregulation of these channels can also contribute to worse outcomes in stroke, neurodegenerative disorders and multiple sclerosis. Studies show that sustained acidosis results in hyperactivity of ASICs, resulting in greater neurotoxicity and much wider brain cell death. Moreover, knocking out these channels in animal studies results in reduced infarct volume, thus leaving little doubt in the importance of these channels in neuronal survival. Moreover, pharmacological blockade of ASIC1a channels can exert neuroprotection for up to eight hours after stroke in animal models. Importantly, it appears that ASICs get more strongly activated during prolonged acidosis by interaction with the endogenous opioid neuropeptide called Big dynorphin (Big Dyn). Thus, targeting this interaction may provide a means to combat ASIC1a-dependent cell death.

To address this, researchers at RWTH Aachen University and Research Center Jülich in Germany: Lilia Leisle, Michael Margreiter, Dr. Audrey Ortega-Ramírez, Elinor Cleuvers, Michèle Bachmann, Giulia Rossetti, and led by Professor Stefan Gründer investigated in detail the interaction of ASIC1a with Big Dyn. Big Dyn is abundant in the brain, but what is important is that researchers have noticed that it increase ASIC1a activity, thus resulting in greater neurotoxicity. Using in silico molecular modelling, one of the advanced computational biology approaches commonly used in drug discovery, the research team found that Big Dyn binds to ASIC1a via electrostatic forces. They also successfully identified 16 sites at ASIC1a protein involved in binding with Big Dyn. The original research article is now published in Journal of Medicinal Chemistry.

There are many important implications of these findings. Since researchers now discovered how Big Dyn binds to ASIC1a, resulting in the channels hyperactivity and neuronal cell death, it is possible to find ways to prevent this binding. Preventing such binding may considerably help minimize brain cells death after stroke or infarction. Additionally, modulating this binding site may help modulate memory and learning.  Furthermore, researchers think that modulating Big Dyn and ASIC1a binding would have much broader implications for treatment of brain diseases. For instance, it may help slow the progress of multiple sclerosis and develop more effective pain killers.