Abnormal levels of catecholamines and more recently the enkephalins in the CNS have been implicated in the generation and manifestation of a variety of neurological and behavioral disorders. Control of the levels of these putative neurotransmitters is dependent, in part, on both their rate of synthesis and their rate of degradation by a variety of enzymatic reactions. As will be described in considerable detail in this grant application, there is mounting evidence to suggest that sulfation by the enzyme or enzymes classified as phenol sulfotransferase (PST) may contribute significantly to the inactivation of the catecholamine neurotransmitters dopamine and norepinephrine in vivo. In addition, PST may also be involved in production of sulfated enkephalines which have recently been shown to be present in significant quantities in rat brain. Interestingly, it has been suggested that this conjugate may protect the enkephalins from proteolytic digestion and thus serve as a storage form of these endogenous opiates. Recent studies in my laboratory have revealed that at least one form of human brain PST is capable of sulfating both the catecholamines as well as the enkephalins and that this reaction may play a more predominant role in humans than previously realized. Accordingly, the major objective of this proposal is to purify, localize and compare differences in the biochemical properties and substrate specificities of the different forms PST in brain. The following specific studies will be performed: 1. Isolate, purify and characterize the different forms of phenol sulfotransferase (PST) from human brain. 2. Prepare species specific polyclonal antibodies to the different forms of PST. 3. Using the species specific antibodies preparations, the location of PST in human brain will be determined immunohistochemically. It is anticipated that these studies will provide us with considerably more insight into the basic mechanisms and the role that sulfation has in contributing to the regulation of catecholamine and enkephalin levels in human brain.
Showing the most recent 10 out of 25 publications
