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    Calcium/CaM-sensitive adenylyl cyclase and its role in neuronal plasticity during learning in Aplysia

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    Author
    Lin, Allison
    Advisor
    Abrams, Thomas W.
    Date
    2010
    Type
    dissertation
    
    Metadata
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    Other Titles
    Ca²⁺/CaM-Sensitive Adenylyl Cyclase and Its Role in Neuronal Plasticity During Learning in Aplysia
    Abstract
    Calmodulin-sensitive adenylyl cyclase (AC) in sensory neurons (SNs) in the marine sea snail, Aplysia, has been proposed as a molecular coincidence detector during conditioning. I identified 4 putative adenylyl cyclases expressed in Aplysia CNS. Calmodulin binds to a sequence in the C1b domain of AC-AplA that resembles the calmodulin-binding sequence in the C1b domain of AC1 in mammals, and also the C1b domain of Ca<super>2+</super>/calmodulin-sensitive rutabaga adenylyl cyclase in Drosophila. rAC-AplA was stimulated by Ca<super>2+</super>/calmodulin. AC-AplC is most similar to the Ca<super>2+</super>-inhibited AC5 and AC6 in mammals. rAC-AplC is directly inhibited by Ca<super>2+</super>, independent of calmodulin. AC-AplA and AC-AplC are expressed in sensory neurons, whereas AC-AplB and AC-AplD are not. Knockdown of AC-AplA demonstrated that serotonin stimulation of cAMP-dependent plasticity in SNs is predominantly mediated by this calmodulin-sensitive adenylyl cyclase. I suggest that the co-expression of a Ca<super>2+</super>-inhibited adenylyl cyclase in SNs, together with a calmodulin-sensitive adenylyl cyclase, would enhance the requirement for coincident Ca<super>2+</super> influx and serotonin for effective stimulation of cAMP levels. When the calmodulin-sensitive adenylyl cyclase is activated by paired Ca<super>2+</super> and serotonin stimuli, activation is most effective when the Ca<super>2+</super> stimulus begins first. This integration of sequential stimuli requires that the modulation of adenylyl cyclase by Ca<super>2+</super>/calmodulin persist after Ca<super>2+</super> levels have declined. Using modeling of calmodulin interactions with adenylyl cyclase, I explored the mechanism that underlies this persistent activation of calmodulin-sensitive adenylyl cyclase. Biochemical assays confirmed predictions of one model in which a target-dependent decrease in the Ca<super>2+</super> dissociation rate of calmodulin underlies to the persistent response of adenylyl cyclase to transient Ca<super>2+</super> stimuli. This is the first suggestion that allosteric effects on the kinetics of Ca<super>2+</super> binding to calmodulin plays a key role in the integration of transient stimuli.
    Description
    University of Maryland in Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2010
    Keyword
    associative learning
    cAMP
    Adenylyl Cyclases
    Aplysia
    Calmodulin
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/924
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