The presence of a comorbid depressive disorder increases risk for morbidity and mortality in patients with coronary heart disease. Serotonergic dysfunction is thought to contribute to mood disorders and is also a risk factor for heart disease, raising the possibility that altered 5-HT homeostasis contribute to comorbidity between neuropsychiatric and cardiovascular disorders. Recently, we discovered a physical and functional interaction between 5-HT transporter (SERT) and integrin ?3 in platelets. While integrin ?3 is essential for platelet function, SERT plays a prominent role in the modulation of neuronal 5-HT signaling. The integrin ?3 polymorphism Leu33Pro is associated with cardiovascular disease due to enhanced integrin signaling and platelet aggregation. This ?3 variant is also associated with hyperserotonemia in autistic patients, due to its upregulation of SERT surface expression and activity. Our preliminary studies indicate that integrin ?3 is expressed presynaptically (as the dimer ?V?3), where it physically associates with SERT. Additional studies suggest that manipulation of ?V?3 signaling directly influences SERT function. These findings lead to my hypothesis that the SERT/ ?V?3 complex represents a critical and conserved facet of synaptic SERT regulation, mimicking its actions in platelets. This proposal seeks 1) to elucidate the physical basis by which ?V?3 influences SERT, 2) to establish the contribution of ?V?3-based activation to SERT regulation and 3) to understand the impact of Leu33Pro ?3 coding variation on SERT function.
In Aim 1, we focus on mapping the ?3 binding domain in SERT utilizing biochemical and in vitro approaches, providing a route to the development of small peptides that can disrupt SERT/ ?V?3 interactions ex vivo.
In Aim 2, we utilize small molecule ?V?3 ligands to delineate the influence of ?V?3 activation on SERT function ex vivo, as well as 5-HT clearance in vivo.
In Aim 3, we determine the effects of the Leu33Pro ?3 variant on 5-HT levels and SERT activity in both platelets and in the brain. We hypothesize that the expression of integrin Pro33?3 will lead to constitutively- elevated SERT function in platelets and brain. Together, these studies represent the first opportunity to examine the presynaptic impact of ?V?3 and help elucidate pathways supporting comorbidity between mental illness and cardiovascular disease.
The proposed project aims to understand how integrins modulate the serotonin system using molecular and biochemical approaches. As mood disorders are associated with impaired information processing, the association between a cell adhesion receptor and the major target for antidepressant therapy reveals a novel mechanism affected by mood disorders. The protein complex studied in detail in this proposal is also a common molecular feature of mood and cardiovascular disease and provides clues to understanding the comorbidities between the two disorders.
|Dohn, Michael R; Kooker, Christopher G; Bastarache, Lisa et al. (2017) The Gain-of-Function Integrin ?3 Pro33 Variant Alters the Serotonin System in the Mouse Brain. J Neurosci 37:11271-11284|
|Oliver, Kendra H; Duvernay, Matthew T; Hamm, Heidi E et al. (2016) Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein ?IIb?3 Activation through Dysregulation of the 5-HT2A Receptor. J Biol Chem 291:20210-9|
|Varney, Seth; Polston, Keith F; Jessen, Tammy et al. (2015) Mice lacking integrin ?3 expression exhibit altered response to chronic stress. Neurobiol Stress 2:51-58|
|Mazalouskas, Matthew; Jessen, Tammy; Varney, Seth et al. (2015) Integrin ?3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice. Neuropsychopharmacology 40:2015-24|
|Whyte, Alonzo; Jessen, Tammy; Varney, Seth et al. (2014) Serotonin transporter and integrin beta 3 genes interact to modulate serotonin uptake in mouse brain. Neurochem Int 73:122-6|
|Oliver, Kendra H; Jessen, Tammy; Crawford, Emily L et al. (2014) Pro32Pro33 mutations in the integrin ?3 PSI domain result in ?IIb?3 priming and enhanced adhesion: reversal of the hypercoagulability phenotype by the Src inhibitor SKI-606. Mol Pharmacol 85:921-31|