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A comparison of the actions of BIBN4096BS and CGRP 8–37 on CGRP and adrenomedullin receptors expressed on SK‐N‐MC, L6, Col 29 and Rat 2 cells
Author(s) -
Hay Debbie L,
Howitt Stephen G,
Conner Alex C,
Doods Henri,
Schindler Marcus,
Poyner David R
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704844
Subject(s) - calcitonin gene related peptide , adrenomedullin , receptor , medicine , endocrinology , calcitonin , chemistry , biology , neuropeptide
The ability of the CGRP antagonist BIBN4096BS to antagonize CGRP and adrenomedullin has been investigated on cell lines endogenously expressing receptors of known composition. On human SK‐N‐MC cells (expressing human calcitonin receptor‐like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1)), BIBN4096BS had a pA 2 of 9.95 although the slope of the Schild plot (1.37±0.16) was significantly greater than 1. On rat L6 cells (expressing rat CRLR and RAMP1), BIBN4096BS had a pA 2 of 9.25 and a Schild slope of 0.89±0.05, significantly less than 1. On human Colony (Col) 29 cells, CGRP 8–37 had a significantly lower pA 2 than on SK‐N‐MC cells (7.34±0.19 ( n =7) compared to 8.35±0.18, ( n =6)). BIBN4096BS had a pA 2 of 9.98 and a Schild plot slope of 0.86±0.19 that was not significantly different from 1. At concentrations in excess of 3 n M , it was less potent on Col 29 cells than on SK‐N‐MC cells. On Rat 2 cells, expressing rat CRLR and RAMP2, BIBN4096BS was unable to antagonize adrenomedullin at concentrations up to 10 μ M . CGRP 8–37 had a pA 2 of 6.72 against adrenomedullin. BIBN4096BS shows selectivity for the human CRLR/RAMP1 combination compared to the rat counterpart. It can discriminate between the CRLR/RAMP1 receptor expressed on SK‐N‐MC cells and the CGRP‐responsive receptor expressed by the Col 29 cells used in this study. Its slow kinetics may explain its apparent ‘non‐competive’ behaviour. At concentrations of up to 10 μ M , it has no antagonist actions at the adrenomedullin, CRLR/RAMP2 receptor, unlike CGRP 8–37 .British Journal of Pharmacology (2002) 137 , 80–86. doi: 10.1038/sj.bjp.0704844