ERK and mTOR signaling couple beta-adrenergic receptors to translation initiation machinery to gate induction of protein synthesis-dependent long-term potentiation.
beta-Adrenergic receptors critically modulate long-lasting synaptic plasticity and long-term memory in the mammalian hippocampus. Persistent long-term potentiation of synaptic strength requires protein synthesis and has been correlated with some forms of hippocampal long-term memory. However, the intracellular processes that initiate protein synthesis downstream of the beta-adrenergic receptor are unidentified. Here we report that activation of beta-adrenergic receptors recruits ERK and mammalian target of rapamycin signaling to facilitate long-term potentiation maintenance at the level of translation initiation. Treatment of mouse hippocampal slices with a beta-adrenergic receptor agonist results in activation of eukaryotic initiation factor 4E and the eukaryotic initiation factor 4E kinase Mnk1, along with inhibition of the translation repressor 4E-BP. This coordinated activation of translation machinery requires concomitant ERK and mammalian target of rapamycin signaling. Taken together, our data identify distinct signaling pathways that converge to regulate beta-adrenergic receptor-dependent protein synthesis during long-term synaptic potentiation in the hippocampus. We suggest that beta-adrenergic receptors play a crucial role in gating the induction of long-lasting synaptic plasticity at the level of translation initiation, a mechanism that may underlie the ability of these receptors to influence the formation of long-lasting memories.
Gelinas
Jennifer N
JN
Departments of Physiology and University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
Banko
Jessica L
JL
Departments of Molecular Physiology and Biophysics and Vanderbilt Medical Center, Nashville, Tennessee 37232.
Hou
Lingfei
L
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, and the.
Sonenberg
Nahum
N
Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Weeber
Edwin J
EJ
Departments of Molecular Physiology and Biophysics and Vanderbilt Medical Center, Nashville, Tennessee 37232; Departments of Pharmacology, Vanderbilt Medical Center, Nashville, Tennessee 37232, the.
Klann
Eric
E
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, and the.
Nguyen
Peter V
PV
Departments of Physiology and University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada; Departments of Psychiatry, and University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada; Centre for Neuroscience, University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada. Electronic address: peter.nguyen@ualberta.ca.
D000818:Animals; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D017774:Long-Term Potentiation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
C491255:Eif4ebp2 protein, mouse; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D011943:Receptors, Adrenergic, beta; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases