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Pharmacology

Our research has two primary aims:

1) To resolve the evolution of important gene families in vertebrates, particularly gene families expressed in the nervous system and in the endocrine system. The purpose is to discover at which point new functions have arisen and how functions have changed during evolution. We are primarily investigating gene families that include neuropeptides, G-protein-coupled receptors, voltage-gated ion channels, and genes involved in vision.

2) To characterize the NPY (neuropeptide Y) system of peptides and G-protein-coupled receptors, and their closest relatives, with regard to ligand-receptor interactions and receptor regulation of importance for appetite regulation.

Many hundreds, perhaps thousands, of vertebrate gene families are now known to have expanded in two dramatic events to have occurred approximately 500 million years ago; namely, two genome doublings or tetraploidizations (called 2R for two rounds of genome duplication). In addition, a third tetraploidization (3R) took place in the ancestor of teleost fishes. These events explain a great deal of the complexity of presently living vertebrates, and also explain functional overlap for members of many gene families. We are using a combination of phylogenetic sequence analysis, and chromosome comparisons across species, to distinguish gene duplication events in gene families of special functional interest. This approach is very useful to identifying corresponding genes (orthologues) in different species for comparisons of functions. The results have important implications for our ability to understand how functions arise, change, and frequently even disappear during evolution. Among the gene families that we have studied, or are presently studying, are the opioid peptides (enkephalins etc.) and their receptors, growth hormone and prolactin and their receptors, oxytocin-vasopressin receptors, somatostatin receptors, voltage-gated sodium and calcium channels, and the gene families involved in signal transduction in the rods and cones of the eye.

 

NPY is one of the most abundant neuropeptides, in the brains of all mammals, including humans. Together with its two related peptides, PYY and PP, it regulates appetite, metabolism and numerous other physiological functions. We are engaged in characterizing the NPY-family peptides and their 4-7 receptors in species representing different vertebrate classes. Our comparative approach aims to delineate the opposing roles of NPY and PYY/PP in appetite, using methods that range from molecular genetics and molecular pharmacology via cell biology to in vivo physiology. We also investigate the correlation of genetic variation in one of the receptor genes with body weight and obesity.

 

Contact

Dan Larhammar

Group leader:

Prof. Dan Larhammar

e-mail: dan.larhammar@neuro.uu.se

 

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