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Lee Limbird, Ph.D.

Professor
Chair of Biomedical Sciences
Vice President for Research, Meharry Medical College
Researcher

Contact Information:

Vanderbilt University Medical Center
417B PRB
Nashville, TN 37232-6600
615-322-2207

Research Specialty

G protein-coupled Receptors: Trafficking, signaling and in vivo function of alpha(2)-adrenergic receptor subtypes

Research Description

Our laboratory studies the structure, cellular and in vivo function, and trafficking of G protein-coupled receptors. The principal model system that we have used for our studies are the alpha(2)-adrenergic receptors (alpha(2)-ARs), which bind epinephrine and norepinephrine and elicit their diverse physiological effects by activation of Gi/Go GTP-binding proteins that regulate various electrical and chemical messengers. Investigation of genetically-modified mice with mutated, or absent, alpha(2)-ARs has revealed the role for the alpha(2A)-AR subtype in multiple physiological functions, including lowering of the blood pressure via the central nervous system, suppression of epileptogenesis, suppression of pain perception, sedation and anesthesic sparing. Continuing studies seek to understand the role of this subtype in a variety of behavioral paradigms, particularly those which link the receptor to roles in depression, attention, and cognition. Furthermore, with the advent of gene profiling and proteomics strategies, we have begun to explore genes and proteins expressed in critical brain regions in wildtype mice versus those lacking the gene expressing the alpha(2A)-AR subtype.

In a parallel line of studies in the laboratory, we are examining the mechanisms by which G protein-coupled receptors achieve their delivery and retention in specialized domains on the surface of target cells. For the alpha(2)-AR subtypes, we have focused primarily on polarized renal epithelial cells, where all three subtypes achieve basolateral localization at steady state, albeit via different trafficking itineraries. Structure-function studies have revealed that receptor sequences embedded in or near the bilayer are involved in receptor delivery to a particular surface, whereas the third intracellular (3i) loop of these three alpha(2)-AR subtypes is involved in tethering to the lateral subdomain. Recently, we have demonstrated that this 3i loop interacts both with 14-3-3 proteins as well as with spinophilin. Current studies are exploring the surface interface between the 3i loops and these interacting proteins as well as determining the functional relevance of these interactions for scaffolding, signaling or termination of signaling. These studies are being carried out both in vitro as well as in vivo, again using genetically-modified mice under development.

To reveal the molecules and machinery involved in G protein-coupled receptor targeting to a particular surface in renal epithelial cells, we have begun to study the V(2) vasopressin receptor system as a model. A variety of mutations within these receptors occur naturally, and lead to the disease X-linked nephrogenic diabetes insipidus. Most of these mutations cause the accumulation of the V(2) receptor intracellularly. Current studies are determining at which partial reaction in receptor synthesis, maturation, and surface delivery a particular mutation leads to V(2) receptor dysfunction; furthermore, we are utilizing mutant V(2) receptors as tools, in expression cloning strategies, to identify the molecules and machinery critical for G protein-coupled receptor delivery to the appropriate surface of polarized cells.

Publications


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