Abstract
The calcium-sensitive type VI adenylyl cyclase (AC6) is a membrane-bound adenylyl cyclase (AC) that converts ATP to cAMP under stimulation. It is a calcium-inhibited AC and integrates negative inputs from Ca2+ and multiple other signals to regulate the intracellular cAMP level. In the present study, we demonstrate that AC6 functions upstream of CREB and negatively controls neuronal plasticity in the hippocampus. Genetic removal of AC6 leads to cyclase-independent and N-terminus of AC6 (AC6N)-dependent elevation of CREB expression, and enhances the expression of GluN2B-containing NMDA receptors in hippocampal neurons. Consequently, GluN2B-dependent calcium signaling and excitatory postsynaptic current, long-term depression, and spatial reversal learning are enhanced in the hippocampus of AC6−/− mice without altering the gross anatomy of the brain. Together, our results suggest that AC6 negatively regulates neuronal plasticity by modulating the levels of CREB and GluN2B in the hippocampus.
Highlights
Adenylyl cyclases (ACs) are a family of enzymes that convert ATP into adenosine 3′,5′ cyclic mononucleotide, an important second messenger that controls cellular functions
We previously reported that the amount of AC6 protein increased in the brain during postnatal development, suggesting that AC6 may be involved in the maturation of hippocampus[5]
Given that cAMP response element-binding protein (CREB) is a downstream target of ACs and has been implicated in the maturation of hippocampus and neuronal plasticity, we assessed the amounts of total CREB and activated CREB in young and adult hippocampus
Summary
Adenylyl cyclases (ACs) are a family of enzymes that convert ATP into adenosine 3′ ,5′ cyclic mononucleotide (cAMP), an important second messenger that controls cellular functions. Deficiencies in AC1 and AC8 impair long-term potentiation (LTP) and memory, suggesting that AC1 and AC8 have important roles in the regulation of synaptic plasticity[2]. The activation of NMDARs triggers multiple signaling pathways that are critical for synaptic plasticity (i.e., LTP; long-term depression, LTD) and learning and memory[6]. We are interested in the regulation of GluN2B by AC6 in the hippocampus because a cAMP response element-binding protein (CREB) binding site is located in the promoter region of GluN2B gene[46] and GluN2B plays a critical role in controlling hippocampal functions during development[10]. We present evidence to demonstrate that AC6 negatively modulates the CREB/GluN2B-mediated synaptic plasticity and LTD in the hippocampus and spatial reversal learning
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