Introduction

The Peripheral Neuropathy Solution

Peripheral Neuropathy Program By Dr. Randall Labrum

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Extracellular potassium ions (K+) have been widely utilized as a tool to study neurotransmitter release from either peripheral or central neurons. Although neurotransmitter released by pulses of the potassium ions appears to have a more limited specificity than that achieved with electrical stimulation, the method is useful in circumstances in which the electrical stimulus may not be adequate. A simple method for the study in vitro of 3H-norepinephrine released from several areas of the central nervous system of the rat has been known for a long time [1]. Under these experimental conditions, the metabolic pathway of the 3H-neurotransmitter resembles that described for 3H-norepinephrine released under conditions of electrical stimulation in the peripheral nervous system. The involvement of neuronal a-adrenoreceptors in a negative feed-back mediated control of norepinephrine release elicited by electrical stimulation from the peripheral nerve endings has been well documented [2,3,4], however the molecular similarity and differences, if any, between the prejunctional receptors (a2) of the central and the peripheral organs remain to be elucidated. Enantiomers of norepinephrine were used to gain some insight into the prejunctional a-Adrenoceptor of rat hypothalamus and the vas deferens. Molecular modeling of the prejunctional a2A-adrenoceptor as well as that of the well known postjunctional a1A-adrenoceptor was used to examine the degree of the selectivity for the receptors. Although no x-ray structure of a1A and a2A-AR have been published yet, but recently published crystal structure of human beta-2 adrenoceptor (hp2-AR) [5] combined with functional, structural and experimental data can produce reliable model of a1A and a2A-AR at atomic resolution. Atomic details of the receptors are needed to gain insight into conformational changes upon receptor activation. In previous studies, it has been shown that agonist binding site is located between TM III, TM V and TM VI (Figure 1A and B) and movement of these TM helices with respect to each other leads to activation of the receptor [6-10]. Previously, it has been also argued that a rotation of TM V is likely to be involved in receptor activation [11,12]. Figure 1B shows SiteMap's predicted ligand binding site at AR. SiteMap (v2.2, Schrodinger, LLC, New York, NY, 2008) uses a novel algorithm for rapid binding site identification and evaluation.

Figure 1. A. Representation of transmembrane helices of adrenoceptors (cartoon drawing of helices) and agonist binding pocket. Agoinst is represented as VWD form in the binding pocked formed by TM III, TM V and TM VI. B. SiteMap's predicted agonist binding pocket between TM III, TM V and TM VI. Yellow wireframe corresponds to hydrophobic pocket and red and blue wireframe corresponds to hydrogen bond acceptor and donor respectively.

Figure 1. A. Representation of transmembrane helices of adrenoceptors (cartoon drawing of helices) and agonist binding pocket. Agoinst is represented as VWD form in the binding pocked formed by TM III, TM V and TM VI. B. SiteMap's predicted agonist binding pocket between TM III, TM V and TM VI. Yellow wireframe corresponds to hydrophobic pocket and red and blue wireframe corresponds to hydrogen bond acceptor and donor respectively.

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