title: PACAP receptor pharmacology and agonist bias: analysis in primary neurons and glia from the trigeminal ganglia and transfected cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  PACAP-responsive receptors in rat trigeminal neurons, glia and transfected PAC1n 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
  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.
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand; Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors.forename: C S
authors.initials: CS
authors.lastname: Walker
authors.forename: T
authors.initials: T
authors.lastname: Sundrum
authors.forename: D L
authors.initials: DL
authors.lastname: Hay
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000819:agonists / Q000187:drug effects*; D014162:Transfection
chemical_list: D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
keywords: G-protein coupled receptor; PAC1; PACAP; VIP; bias signalling; glia; intracellular signalling; neuron; primary culture; trigeminal ganglia