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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Dopamine Channels with Applications

Dopamine molecules, by combining different sub-types of dopamine receptors, regulate the motor function, cognitive activity, and emotions of living organisms, which are closely related to the pathology and treatment of Parkinson's disease and schizophrenia(Ye, et al. 2013; Li, et al. 2017; Xie, et al. 2017). In vivo, the production of dopamine molecules is by midbrain dopaminergic neuronal tissue. In the substantia nigra tissue, dopamine molecules are produced in the dopaminergic neuron cells of the anterior membrane, and the produced dopamine molecules packaged by the vesicles are released into the intercellular space through the cell membrane. At the intercellular space, various dopamine receptors are present on the dopaminergic neuron cell membranes of the posterior membrane cells. These receptors can accept the binding by dopamine molecules to exert dopamine function. However, dopamine molecules placed in the intercellular space had long been not cared. No one had studied the actual part of the dopamine receptors for dopamine molecules to act. No one had studied for dopamine molecules how to work actually. And no one had studied the presence of dopamine molecular pathways throughout the dopamine receptors. We have used the dopamine third receptor crystal structure(Chien, et al. 2010), to study the complex structure of the dopamine molecule with third receptor protein, to study and obtain the dopamine active pocket that exert the functions(Jin, et al. 2011), and to study and obtain dopamine molecular channels within the dopamine receptor structures(Li, et al. 2017).

There are two types of dopamine molecular channels within the dopamine receptor to be found by us, one is "dopamine functional channel" and the other is "dopamine protective channel". Then we have further proved the existence of "dopamine functional channel" and the existence of "dopamine protective channel" by a combination of molecular dynamics experiments and animal experiments.

Due to the presence of dopamine functional channel, the dopamine molecules released into the intercellular space can be divided into two categories. A class of dopamine molecules that can reach the functional sites through the dopamine functional channel can truly function as a signal transduction and regulation. These functional dopamine molecules are called "functional dopamine." In addition, another class of dopamine molecules, which are non-functional dopamine molecules, will be reabsorbed or decomposed. Obviously, functional dopamine occupies a small fraction of total dopamine, similar to drinking water occupying a small fraction of total water. The relationship between functional dopamine content and total dopamine content, we have studied to establish a formula to represent:

GD = f × TD (1)


Wherein GD is a functional dopamine content; TD is the total dopamine content (expressed as a percentage); f is the dopamine functionalization factor, which is the ratio of total dopamine converted to functional dopamine, normalized to 1 as a value for normal healthy persons.

Based on the above formula (1), we have clarified the essence of Parkinson's disease to be the lack of functional dopamine, and proposed the scientific pathology of Parkinson's disease that is a significant reduction in functional dopamine to cause Parkinson's disease. We can scientifically name Parkinson's disease as "Functional dopamine deficiency syndrome." According to the scientific pathology of Parkinson's disease, all types of Parkinson's disease can be included and confirmed without misdiagnosis and missed diagnosis. According to the scientific pathology of Parkinson's disease, new drugs for treating Parkinson's disease can be found. Depending on the types of Parkinson's disease, different therapy programs and new drugs can be used able to cure the disease of patients with early and mid-stage Parkinson's disease, and feasibly better to control patients with the late advanced Parkinson's disease for keeping better symptoms. Our research can make Parkinson's disease from a difficult, complex, incurable and uncontrollable disabling disease changed to be a simple, curable or controllable disease, although it cannot be eradicated at present.

Support from the National Natural Science Foundation of China (21163024, 21563032).

References

    Chien, E. Y. Liu, W. Zhao, Q. Katritch, V. Han, G. W. Hanson, M. A. Shi, L. Newman, A. H. Javitch, J. A. Cherezov, V. & Stevens, R. C. (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091-1095.

    Jin, Y. Wang, Y. Bian, F. Y. Shi, Q. Ge, M. F. Wang, S. Zhang, X. K. & Xu, S. C. (2011) Three-dimensional structure of dopamine 3-subtype receptor with the active site residues for the binding of dopamine. Acta Phys-Chim Sin 27, 2432-2446.

    Li, A. Xie, W. Wang, M. & Xu, S. C. (2017). Molecular Dynamics of Dopamine to Transmit through Molecular Channels within D3R. Acta Phys-Chim Sin 33, 927-940.

    Xie, W. Wang, M. Li, A. & Xu S C. (2017) Molecular dynamics simulation of d-benzedrine transmitting through molecular channels within D3R. J Biomol Struct Dyn 35, 1672-1684.

    Ye, N. Neumeyer, J. L. Baldessarini, R. J. Zhen, X. C. & Zhang, A. (2013). Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. Chem Rev 113, PR123-PR178.

Zhengqiong Zhang,
Xiaowen Zhou,
Zeren Xu,
Chengqi Lu,
Sichuan Xu*

College of Chemical Science and Technology and Pharmacy
Yunnan University
Kunming 650091, P. R. China

*Email: sichuan@ynu.edu.cn