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The role of Ca²⁺-stimulated adenylyl cyclases in bidirectional synaptic plasticity and brain function
1Department of Physiology, Neuroscience Program, 2201 BPS Building, Michigan State University, East Lansing, MI 48824, USA. wangho@msu.edu
Abstract:
The activity-dependent neuronal modification is important for many aspects of adaptive behavior and brain development. Very often, neurological disorders are associated with the alteration of neural signaling pathways that are required for activity-triggered cellular events. Mounting evidence has implicated the role of cyclic AMP (cAMP)-cAMP-dependent protein kinase (PKA)-ERK1/2-cAMP-responsive element-binding protein (CREB) cascade in numerous brain functions such as learning and memory. Ca2+-stimulated type 1 and type 8 adenylyl cyclases (AC1 and AC8) are unique enzymes that couple activity-dependent calcium influx to the activation of cAMP signaling. Here, we summarize some direct evidence to support that Ca2+-stimulated cAMP signaling regulates molecular and cellular substrates of neuronal adaptation. Specifically, the function of AC1 and AC8 in synaptic functions, such as long-term potentiation, long-term depression, and depotentiation, has been examined by using genetic deletion and overexpression approaches. Consistent with the current hypothesis, the Ca2+-stimulated cAMP production through AC1 and AC8 is required for the activity-dependent activation of the ERK1/2-CREB cascade. We further describe the phenotypes of AC1/AC8 mutant mice in memory formation and other adaptive brain functions. The findings may suggest Ca2+-stimulated AC as therapeutic target for the treatment of mental retardation, pain, addiction, anxiety, depression, and neurodegeneration.
Insights
Calcium-stimulated adenylyl cyclases (AC1 and AC8) are crucial for cyclic AMP (cAMP) signaling, regulating neuronal adaptation and adaptive behaviors. Targeting these enzymes may offer new treatments for various neurological and psychiatric disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Signaling
Background:
- Activity-dependent neuronal modification is vital for adaptive behavior and brain development.
- Neurological disorders often involve altered neural signaling pathways essential for activity-triggered cellular events.
- The cyclic AMP (cAMP)-cAMP-dependent protein kinase (PKA)-ERK1/2-cAMP-responsive element-binding protein (CREB) cascade is implicated in learning and memory.
Purpose of the Study:
- To summarize evidence on how Ca2+-stimulated cAMP signaling regulates molecular and cellular substrates of neuronal adaptation.
- To examine the function of adenylyl cyclases 1 and 8 (AC1 and AC8) in synaptic plasticity.
- To describe the phenotypes of AC1/AC8 mutant mice in memory and adaptive brain functions.
Main Methods:
- Genetic deletion and overexpression of AC1 and AC8.
- Investigation of synaptic functions including long-term potentiation, long-term depression, and depotentiation.
- Analysis of memory formation and adaptive brain functions in AC1/AC8 mutant mice.
Main Results:
- Ca2+-stimulated cAMP production via AC1 and AC8 is essential for the activity-dependent activation of the ERK1/2-CREB cascade.
- AC1 and AC8 play critical roles in synaptic plasticity.
- AC1/AC8 mutant mice exhibit altered memory formation and adaptive brain functions.
Conclusions:
- Ca2+-stimulated cAMP signaling through AC1 and AC8 is a key regulator of neuronal adaptation.
- These findings highlight the therapeutic potential of Ca2+-stimulated adenylyl cyclases for treating neurological and psychiatric conditions.
- Targeting AC1 and AC8 may offer novel therapeutic strategies for mental retardation, pain, addiction, anxiety, depression, and neurodegeneration.
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