Cyclic AMP (cAMP) in Learning and Memory

Introduction of cAMP

The full name of cAMP is cyclic adenosine 3’,5’-monophosphate. cAMP was the first messenger to be found. There are three main effectors of cAMP: PKA which phosphorylates numerous metabolic enzymes, EPAC which is a guanine-nucleotide-exchange factor, and cyclic-nucleotide-gated ion channels. cAMPs exert essential roles in cellular responses to many hormones and neurotransmitters. The levels of cAMP in cells are regulated by the balance between the activities of two enzymes, cyclic nucleotide phosphodiesterase (PDE) and adenylyl cyclase (AC). These enzymes possess different isoforms which are encoded by many genes. These enzyme genes have different expression patterns and mechanisms of regulation, thereby inducing cell-type and stimulus-specific responses.

cAMP Signaling Pathway

AC enzyme, an integral membrane protein, is composed of two transmembrane domains, each of which has six transmembrane α helices. There are two catalytic domains in the cytoplasmic surface of the cell membrane, in which there are two conserved sequences C1A and C2A, which are mainly responsible for the activity of AC. The α subunit of the Gs protein binds to and activates AC, leading to the conversion of adenosine triphosphate (ATP) into cAMP. The increased cAMP levels could activate several effectors, of which the most well-described is cAMP-dependent protein kinase (PKA). When the levels of intracellular ATP, two cAMP molecules bind to each R subunit, leading to the dissociation of the C subunits and rapid kinase activation. The activation of PKA subsequently phosphorylates the protein to elicit cellular responses.

PDE is revealed to catalyze the hydrolysis of intracellular second messenger molecules, including cAMP and cGMP. Inhibition of PDE activation can indirectly increase the level of intracellular cAMP.

cAMP signaling pathways are associated with many conditions and diseases, including inflammation, cancer, myocardial atrophy, and depression. Importantly, cAMP signaling pathways have been reported to regulate synapses during learning and be associated with learning and memory.

Fig.1 cAMP neuron pathway.

Role of cAMP in Learning and Memory

cAMP/PKA/CREB signaling pathways play important role in the process of learning and memory. In recent years, numerous studies have been conducted on animals to describe the association of cAMP/PKA/CREB signaling and learning and memory.

• cAMP/PKA protein

cAMP is an intracellular second messenger molecule that phosphorylates PKA and is involved in many biological processes, such as gene expression, cell growth, and differentiation. In mammal, PKA has 4 R subunits (RIα, RIβ, RIIα, and RIIβ) and 3 C subunits (Cα, Cβ, and Cγ). Each subunit has been found expression in neurons, especially, PKA-Cβ is highly expressed in neurons, which is required for synaptic plasticity. Studies have revealed the C subunits play an essential role in long-term synaptic plasticity and long-term potentiation.

• CREB protein

CREB, a cAMP-response element binding protein, is an intracellular regulator that regulates transcription through autophosphorylation. CREB can integrate the signals induced by calcium ions, growth factors, and cAMP. It plays an important role in learning and memory as well as the normal regulation and maintenance of various emotions. In the nervous system, CREB is an important component of multiple intracellular signaling pathways, whose downstream effects include affecting the survival and growth of neurons, the plasticity of synapses, and the formation of long-term memory. The decreased activity of CREB could inhibit the formation of long-term memory, while the increased activity could promote the formation of long-term memory. Besides, the downstream protein CREB regulated by cAMP is involved in the formation of learning and memory impairment induced by ketamine in juvenile rats.

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