ISSN:
1432-1912
Keywords:
Key words 5-HT3 receptors
;
Brainstem
;
Colon
;
Entorhinal cortex
;
Salivary gland
;
[3H]-granisetron
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The affinities of a range of structurally diverse 5-HT3 receptor agonists and antagonists for [3H]-granisetron binding sites have been measured in membrane homogenates prepared from central and peripheral tissues of the mouse. By comparing the affinities of compounds across these tissues, the question of whether intra-species 5-HT3 receptor subtypes exist in the mouse has been addressed. In entorhinal cortex and brainstem, [3H]-granisetron bound to a single high affinity saturable binding site (Kd 0.47±0.14 and 0.60±0.05 nM; B max 20±6 and 7±2 fmol (mg protein)-1 respectively; mean± SEM; n=3). In distal and proximal colon, the specific binding of [3H]-granisetron was best fitted to a 2-site model. Kd values obtained for the high affinity site were similar to those obtained in brain tissue (distal colon: 0.47±0.09 nM, n=4; proximal colon: 0.39±0.09 nM, n=4). In salivary gland, 2-sites were evident in 2 out of 4 experiments. The Kd value (calculated from the high affinity site in the 2-site model) was approximately 10-fold less than in brain or colon (3.3±1.1 nM, n=4). B max values were 7±2, 4±1 and 71±16 fmol (mg protein)-1 for distal colon, proximal colon and salivary gland respectively. For all tissues the estimated affinity of the low affinity site was variable, and B max values could not be reliably calculated. Extensive comparative studies performed with 17 different 5-HT3 receptor agonists and antagonists in the five tissues did not reveal differences in affinity for any compound between the entorhinal cortex and the brainstem nor between the two regions of the colon. However, MDL72222, R-zacopride, d-tubocurarine, and GR80284 apparently had significantly lower affinity for colon than brain binding sites. Also, MDL72222, 2-methyl-5-HT, GR80284, 1-(m-chlorophenyl)-biguanide, metoclopramide, and granisetron had significantly lower affinity for the salivary gland binding sites than the brain binding sites. In an attempt to replicate these observations, we conducted a second study using the compounds which had shown the largest inter-tissue differences in affinity keeping as many variables as possible constant. Simultaneous comparative assays on entorhinal cortex, colon and salivary gland homogenates taken from the same mice showed that the differences that were apparent in the initial comparative study were not maintained. In conclusion, we can find no clear evidence for the existence of tissue-specific subtypes of the 5-HT3 high affinity binding site for [3H]-granisetron in the mouse in the tissues tested. However, a low affinity binding site for [3H]-granisetron was detected in peripheral tissues.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00233240
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