Martin J. Kelly, PhD
SOM-Physiology & Pharmacology Department
Background & Education
Ph.D., University of Texas Southwestern Medical School, 1976
The gonadal steroid estrogen is a pleiotropic hormone that has widespread actions not only on reproductive tissues but also has pronounced effects in the central nervous system (CNS). For over twenty-five years, my laboratory has been studying the actions of estrogen in the brain, specifically in hypothalamic neurons that control homeostasis and behavior, using molecular, electrophysiological and behavioral techniques. We have discovered a novel estrogenic signaling pathway that can better explain the differences between females and males, not only in terms of the reproductive cycle but also differences in stress responses, motivation and mood. These actions of estrogen are similar to the effects of neurotransmitters like serotonin in the CNS. We use an in vitro slice preparation to do whole-cell patch recording in hypothalamic neurons followed by single cell reverse transcription-polymerase chain reaction (RT-PCR) to identify changes in the expression of receptors and K+ channel transcripts during different physiological states.
In collaboration with Drs. Oline Ronnekleiv and Tom Scanlan in the Department, we have developed a new non-steroidal compound that mimics the actions of estrogen in POMC neurons called STX. We have discovered that estrogen acts directly on these neurons via a novel estrogen G protein-coupled receptor to alter their activity. This unique membrane-associated estrogen receptor is Gq-coupled to activation of a phospholipase C-protein kinase C-protein kinase A pathway leading to desensitization of m-opioid and GABAB receptors in POMC and GABA neurons. We use two different experimental models. One model is the female guinea pig whose reproductive cycle mimics that of the human. Another model is the transgenic female mouse in which POMC neurons are tagged with green fluorescence protein in order to selectively target these neurons in the brain slice preparation. Using these models we are working to identify the phosphorylated target proteins (e.g. K+ channel) that are mediating the desensitized response to µ-opioid and GABAB receptor agonists.
As proof of principle, estrogen is known to control feeding behavior, energy and temperature homeostasis, and STX mimics these effects in female guinea pigs. The decrease in body weight gain by STX indicates that estrogen controls body weight gain through in part, the membrane estrogen receptor.
Finally, we also utilize a custom brain-specific guinea pig microarray chip, developed in collaboration with Dr. Oline Ronnekleiv, to characterize the effects of estrogen on gene regulation in relevant hypothalamic nuclei. We have used this gene chip to identify genes important for neuronal excitability (K+ channels) and signal transduction that are regulated by estrogen treatment in female guinea pigs.