Premium
PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells
Author(s) -
Walker C S,
Sundrum T,
Hay D L
Publication year - 2014
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 - 10.1111/bph.12541
Subject(s) - agonist , receptor , neuropeptide , g protein coupled receptor , neuroscience , cell type , vasoactive intestinal peptide , pituitary adenylate cyclase activating peptide , biology , transfection , in vivo , pharmacology , microbiology and biotechnology , cell , cell culture , biochemistry , genetics
Background and Purpose A major challenge in the development of new medicines targeting GPCRs is the ability to quantify drug action in physiologically relevant models. Primary cell models that closely resemble the clinically relevant in vivo site of drug action are important translational tools in drug development. However, pharmacological studies in these models are generally very limited due to the methodology used. Experimental Approach We used a neuropeptide system to demonstrate the applicability of using highly sensitive signalling assays in primary cells. We quantified the action of pituitary adenylate cyclase‐activating peptide ( PACAP )‐38, PACAP ‐27 and vasoactive intestinal polypeptide in primary cultures of neurons and glia derived from rat trigeminal ganglia ( TG ), comparing our observations to transfected cells. Key Results PACAP ‐responsive receptors in rat trigeminal neurons, glia and transfected PAC 1n receptors were pharmacologically distinct. PACAP ‐38, but not PACAP ‐27, activated ERK in glia, while both forms stimulated cellular cAMP production. PACAP (6–38) also displayed cell‐type‐dependent, agonist‐specific, antagonism. Conclusions and Implications The complexity of PACAP pharmacology in the TG may help to direct, more effectively, the development of disease treatments targeting the PACAP receptor. We suggest that these methodologies are broadly applicable to other primary cell types of human or animal origin, and that our approach may allow more thorough characterization of ligand properties in physiologically relevant cell types.