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Principal Investigator: JOHANNES W HELL
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $113,064
Funding agency: National Institute on Aging
Abstract
Supplement to Parent Grant Dysregulation of Cav1.2 by beta amyloid peptide
L-type Ca2+ channels (LTCC) are key regulators of gene transcription, neuronal excitability, and synaptic
functions. Cav1.2 is the prevalent LTCC in brain (Hell et al., 1993, JCB 123, 949-962). Chronically increased
Ca2+ influx via LTCCs has been implicated early on in senile symptoms and Alzheimer’s disease (AD) (e.g.,
Science 272, 1017). We found that aged rats have significantly increased PKA-mediated phosphorylation of
Cav1.2 on Serine 1928 (Davare and Hell, 2003, PNAS 100, 16018-23), which increases Cav1.2 channel activity
(Qian, …, Hell, 2017, Sci Sig 10, eaaf9659). We also found that Cav1.2 forms a unique signaling complex with
the b2 adrenergic receptor (b2 AR) (e.g., Davare et al., 2001, Science 293, 98), making Cav1.2 a prime target for
b2 AR signaling. Oligomeric b amyloid peptide 1-42 (Abo) stimulates the b2 AR. Our supportive evidence indicates
that Abo increase Cav1.2 activity via the b2 AR and the ensuing S1928 phosphorylation. Aim 1 is to test whether
Cav1.2 dysregulation by Abo via Cav1.2-associated b2 AR occurs in dendrites and spines (Ca2+ imaging) and
whether blocking this signaling alleviates Abo neurotoxicity. Aim 2 is to test whether Abo - b2 AR - S1928
signaling stimulates surface insertion of Ca2+ permeable (CP) AMPARs (GluA1 homomers) and blocking CP-
AMPARs alleviates Abo neurotoxicity. Aim 3 will test the role of Abo - b2 AR - S1928 signaling in augmentation
of long-term depression (LTD) by Abo, and in long-term potentiation, which is impaired by Abo. We recently
proved that S1928 phosphorylation downstream of endogenous
During our work on LTD we realized that in adult mice it can only readily be induced during evening and night
hours, the active phase of mice. We then found that S1928 phosphorylation downstream of endogenous
norepinephrine (NE) signaling is strictly required for LTD. For the Supplement we propose to test the emerging
hypothesis that LTD in adult mice has a circadian rhythm that is driven by the established increase NE during
active (night) phase and acts via b2 AR – S1928 signaling. The candidate Adejia Boutté will be central to execute
the electrophysiology.
Terms: <21+ years old><AD dementia><AD/HD><ADHD><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adrenergic Receptor><Adrenoceptors><Adult><Adult Human><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimers Dementia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Attention><Attention deficit hyperactivity disorder><Aβ><Brain><Brain Nervous System><Catecholamine Receptor><Cell Communication and Signaling><Cell Signaling><Chronic><Circadian Rhythms><Common Rat Strains><Complex><Cyclic AMP-Dependent Protein Kinases><Dendrites><Electrophysiology><Electrophysiology (science)><Encephalon><Epinephrine Receptors><Gene Expression><Gene Transcription><Genetic Transcription><Hour><Image><Impairment><Intracellular Communication and Signaling><L-Serine><Levarterenol><Levonorepinephrine><Ligands><Long-Term Depression><Long-Term Potentiation><Long-Term Synaptic Depression><Longterm Potentiation><Mediating><Mice><Mice Mammals><Molecular><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Noradrenaline><Norepinephrine><Nyctohemeral Rhythm><PKA><Pathway interactions><Permeability><Phase><Phosphorylation><Predominantly Hyperactive-Impulsive Type Attention-Deficit Disorder><Predominantly Hyperactive-Impulsive Type Hyperactivity Disorder><Primary Senile Degenerative Dementia><Protein Kinase A><Protein Phosphorylation><RNA Expression><Rat><Rats Mammals><Rattus><Receptor Signaling><Regulation><Regulator Genes><Role><Science><Senility><Serine><Signal Transduction><Signal Transduction Systems><Signaling><Surface><Symptoms><Testing><Transcription><Transcriptional Regulatory Elements><Twenty-Four Hour Rhythm><Wakefulness><Work><a beta peptide><abeta><adenoreceptor><adulthood><aged><alertness><amyloid beta><amyloid peptide><amyloid-b protein><beta amyloid fibril><beta-2 Adrenergic Receptors><biological signal transduction><cAMP-Dependent Protein Kinases><circadian><circadian process><daily biorhythm><electrophysiological><imaging><longterm depression><longterm synaptic depression><neuron toxicity><neuronal><neuronal excitability><neuronal toxicity><neurotoxicity><parent grant><pathway><peptide L><primary degenerative dementia><regulatory gene><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><synapse function><synaptic function><trans acting element><β-2 Adrenoceptor><β2 Adrenergic Receptor>