Receptor Pharmacology

Signal transduction and control of neurotransmission

At the moment, our focus is mostly on a class of receptors called the imidazoline receptors. These are novel family of receptors present on neurons and other tissues and have been named imidazoline receptors because of their high affinity for ligands with an imidazoline or oxazoline structure. Imidazoline receptors exist as multiple subtypes with two principal subtypes having been identified on the basis of ligand binding . I₁-receptors have high affinity for the imidazolines clonidine and moxonidine and low affinity for the imidazolines idazoxan and 2-(benzofuranyl)-2-imidazoline. I₂-receptors have the reverse order of affinity. The I₁-receptor is mainly expressed in the brain and are prevalent in the brainstem, in the rostral ventrolateral medulla (a critical part of the baroreflex arc that controls blood pressure), as well as the hippocampus (important in formation of memories and learning). Our research is directed at the I₁-receptor

The signal transduction system activated by I₁-receptors is not clear, however, stimulation of phosphatidyl-choline specific phospholipase C, has been implicated in PC-12 cells. The structure of IRAS-1 gives us some clues to possible signal transduction mechanisms. IRAS-1 has an SH3-like domain, which suggests that it capable of binding too, and possibly activating tyrosine kinases. Tyrosine kinases in turn are the commonest activators of phosphatidyl-choline specific phospholipase C. We have recently shown that I1-receptor ligands stimulate tyrosine phosphorylation of proteins in PC-12 cells. The challenge is now to confirm that this is an I₁-receptor-mediated effect, and what the targets of phosphorylation are. Also, it is important to determine whether the physiological effects of imidazoline ligands on neurotransmission and neuroprotection are mediated through these pathways.