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Unruly protein may shape learning and memory

By Emily Zhou
September 2010

John Hepler, Ph.D.
Hepler emphasized that "recent studies, including our own, indicate that neurotransmitter GPCR and G proteins engage a growing list of newly appreciated yet poorly understood proteins and linked signaling pathways to carry out their cellular functions." (Photo courtesy of Steve McCaw)

Serena Dudek, Ph.D.
When Dudek, above, was nominated for a Society of Biological Psychiatry award in 2009, Acting Chief of the NIEHS Laboratory of Neurobiology David Armstrong, Ph.D., described her as "one of the youngest luminaries in one of the most dynamic and distinguished fields in neuroscience." (Photo courtesy of Steve McCaw)

In an Aug. 4 seminar at NIEHS, neurobiologist John Hepler, Ph.D., shared exciting findings about a protein found in the mouse hippocampus, where spatial learning and memory formation occur. Part of Hepler's research is in collaboration with NIEHS Synaptic and Developmental Plasticity Group Principal Investigator Serena Dudek, Ph.D., investigating how expression of the regulator of guanine nucleotide binding protein (G protein) signaling 14 (RGS14) may regulate the synaptic plasticity involved in learning and the formation of memories.

Dudek hosted Hepler's discussion of "RGS14 as a novel integrator of unconventional G protein and MAPkinase signaling important for hippocampal function," as part of the Laboratory of Neurobiology Seminar Series. Together, the Hepler ( Exit NIEHS and Dudek labs have shown that RGS14 acts as a natural suppressor of CA2 synaptic transmission and of hippocampal spatial learning and memory.

Previous studies by the Hepler lab have advanced the understanding of emerging signaling mechanisms of G proteins and RGS proteins. More recently, the group's efforts have focused on novel functions of RGS proteins as integrators of receptor and G protein signaling.

Hepler and his colleagues are currently exploring several aspects of RGS protein biology, including signaling roles of RGS proteins in isolated primary hippocampal neurons and slices; regulated dynamic localization of RGS proteins in neurons; RGS protein regulation of spine and dendrite morphology and associated behavioral outputs; and RGS regulation of receptor signaling in neurons and glia.

RGS14 - not a well-behaved RGS protein

According to Hepler, the established model for G protein signaling pathways proposes that hormone- and neurotransmitter-stimulated receptors activate heterotrimeric G proteins (Gα and Gβγ subunits) to elicit responses on downstream effectors. To accelerate the rate of guanine triphosphate (GTP) hydrolysis, RGS proteins serve as GTPase activating proteins (GAPs) that bind to active Gα-GTP, thereby returning Gα to the inactive Gα-GDP form and terminating G protein signaling to effectors.

All RGS protein family members share an RGS domain, but differ in the presence of other unique domains. RGS14 contains an RGS domain that interacts with active Gαi/o and a GPR/GoLoco motif that interacts with inactive Gαi1/3. According to Hepler, RGS14 is not "well behaved" because it can bind both active and inactive Gα subunit.

RGS14 - the memory gene

Immunohistochemistry and in situ hybridization analyses by the Hepler lab used staining to show the presence of RGS14 protein and mRNA in the mouse hippocampus, where spatial learning and memory formation occur. Hepler also demonstrated that knockout mice lacking the RGS14 gene/protein show a marked enhancement in spatial learning and enhanced object memory, with no differences in open-field locomotor, startle reflex, and anxiety behaviors that are not dependent on hippocampal synaptic plasticity.

Further experiments by the Hepler lab found evidence that RGS14 is most highly enriched at postsynaptic spines and dendrites of pyramidal neurons of the enigmatic Cornu Ammonis 2 (CA2) region of the hippocampus.

RGS14 integrates unconventional G protein and MAPkinase signaling

In searching for signaling mechanisms responsible for this RGS14 learning phenotype, Hepler and colleagues determined that RGS14 acts as a scaffold that binds both H-Ras and its effector Raf kinases. By doing so, RGS14 inhibits growth factor mediated MAPkinase signaling through sequestering Ras and Raf. However, when inactive Gα binds RGS14, the conformation of RGS14 protein changes so that it no longer can bind Ras and Raf, allowing its signaling to MAPkinase.

Since H-Ras/Raf and ERK signaling are important for synaptic plasticity, Hepler postulates that RGS14 serves as a scaffold that integrates and modulates Gαi and Ras/Raf/ERK-signaling in the CA2 to regulate synaptic plasticity, learning, and memory. In one of his lighter moments, Hepler suggested that Homer Simpson's stupidity might result from his fully functional RGS14 phenotype, while his bright and multi-talented daughter, Lisa, might have an RGS14 knockout phenotype.

(Yixing [Emily] Zhou, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)

Ties to Chapel Hill and NIEHS

Hepler earned his Ph.D. in neurobiology at the University of North Carolina at Chapel Hill where he trained with a distinguished scientist in G protein signaling, Kenan Professor T. Kendall Harden, Ph.D. Hepler then moved to the University of Texas Southwestern Medical Center for a postdoctoral fellowship with Alfred G. Gilman, M.D., Ph.D., who shared the 1994 Nobel Prize in Medicine, for the discovery of G proteins, with Martin Rodbell, Ph.D., of NIEHS.

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