Bio
Molecular Studies of the 5-HT6 Serotonin Receptor:
Serotonin receptors are involved in multiple brain functions including those giving rise to psychiatric illness. They are part of the G-protein linked superfamily of receptors in which agonist binding triggers a signal cascade which begins binding and activation of a G-protein, leading to signal amplification and a series of cellular processes which differ depending on the types of cells, receptors, and G-proteins involved. I am currently studying the 5-HT6 receptor, a newly described serotonin receptor member with very high affinity for the atypical neuroleptic clozapine. 5-HT6 is highly expressed in the striatum, suggesting that it may be responsible for the lack of extrapyramidal side effects of clozapine and related compounds. There are naturally occurring mutations in G-protein lined receptors which can cause them to become constitutively active, i.e. remain 'turned on' and activate G-proteins even in the absence of agonist. Determining to what extent 5-HT receptors such as 5-HT6 can become constitutively active through mutations is a first step towards exploring whether this mechanism could play a role in diseases involving the serotonergic system.
The Role of the 5-HT7 Serotonin Receptor in the Decay of Circadian Rhythms in Aging and Alzheimer's disease:
Sleep disorders rise with advancing age and particularly affect patients with Alzheimer's disease in whom the degree of sleep disturbance closely parallels the level of dementia and is significantly related to daytime behavioral disturbance. Multiple lines of evidence point towards a malfunction in the circadian pacemaker located in the suprachiasmatic nucleus (SCN) as cause for these changes. Our goal is to help characterize these changes in the central pacemaker which will aid in the eventual development of therapies such as replacement strategies to treat affected patients. The age-related deterioration in circadian rhythms may be related to changes in 5-HT7 receptor expression in the SCN. We plan to investigate the precise localization of 5-HT7 receptor expression in the SCN and characterize changes in expression related to age and Alzheimer's disease.
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