Dopamine and somatostatin are two major neurotransmitter systems that share a number of structural and functional characteristics. Dopamine plays a crucial role in a variety of diseases such as Parkinson's disease, schizophrenia and depression, and somatostatin is involved in modulating many of the actions of dopamine such as dopamine-mediated control of motor activity. Receptors for dopamine and somatostatin are frequently located on the surface of the same neuron, thus providing grounds for believing that there is a physiologically relevant interaction between the two systems, both normally and in diseases such as Parkinson's disease, schizophrenia and depression. However, the molecular basis for such interaction is unclear.
In the April 7, 2000 issue of Science, a team of scientists led by Dr. Yogesh Patel, Director of the Division of Endocrinology at the Royal Victoria Hospital and Professor in the McGill Departments of Medicine, Pharmacology and Therapeutics, Neurology and Neurosurgery, shows how this direct intra-membrane association works.
"Many hormones and neurotransmitters regulate cell function by activating surface receptors that belong to a class of proteins known as G protein-coupled receptors (GPCRs) of which there are an estimated 1000 or more in the body," explains Dr. Patel. " In general, GPCRs have been thought to function as single molecules or monomers to which a hormone binds. We have discovered that when a GPCR is activated by its ligand (i.e. its specific hormone or transmitter) it may join physically with another GPCR belonging to a different receptor family to form a hetero-oligomer, a novel receptor whose properties are distinct from that of the two separate receptors."
In Science, Dr.Patel and his team describe an oligomer of dopamine and somatostatin receptors which can be activated to a certain level by either somatostatin or dopamine but which produces a synergistic response when the two ligands are applied simultaneously. "When the complex is exposed to a dopamine antagonist, signaling from both receptors is inhibited," says Dr. Patel. " It is suspected that there are many undiscovered novel receptors like these in the brain and elsewhere in the body made up of hetero-oligomers whose properties are different from those of individual monomers."
"Now," says Dr. Patel," because of the belief that GPCRs are monomers, our current drugs are aimed at monomers, but if we could design future drugs targeted at any of a number of potential hetero-oligomeric receptor combinations such as dopamine and somatostatin receptors, somatostatin and opioid receptors, dopamine and opioid receptors, we could open the door to new drug treatments for many disorders such as Parkinson's disease, schizophrenia, depression, drug addiction, and severe pain."
Journal
Science