Cyclic amp signaling pathway7/2/2023 ![]() The regulation of the hypothalamic-pituitary-adrenal (HPA) and autonomic nervous system via signal transduction pathways such as PKA and PKC, may be important in the expression of genes that contain cAMP in their promoters, which include key proteins that regulate the stress response in the brain (e.g. PKA functions as a mediator and communicator of cAMP effects to mitogen-activated protein kinases, and protein kinase C (PKC) and B pathways. Robinson-White and Stratakis described PKA signaling as a ‘central hub' which interacts with various other signaling pathways in endocrine cells. The mechanisms of PKA involved in fear memory consolidation and neural plasticity include a wide range of cellular processes, including the activation of CREB and other transcription factors involved in the regulation of de novo protein synthesis required for long-term memory formation, and interaction with various intracellular signaling cascades and receptors. There is now ample evidence to support that fear memories can form quickly and may be difficult to eliminate. Since then, the role of PKA in fear memory formation has been characterized in different processes in several species ( Aplysia, Drosophila, mouse, chick, and rat). G Proteins in Modulating PKAĪbel and Kandel's seminal work on cellular mechanisms of gill-withdrawal memory formation reflex in Aplysia identified the central role of PKA in the process of memory formation. The α- and βγ-subunits can then activate various effectors to moderate cellular responses. The α-subunit binds to GTP, leading to the generation of α-GTP and a βγ-subunit dimer. The binding of agonists to receptors causes an interaction of receptors with G proteins, which, in turn, releases GDP in an exchange with guanosine triphosphate (GTP). The α-subunit confers receptor-effector specificity to G proteins, whereas the γ- subunit has a G protein-specific recognition site. Both α- and βγ-subunits can interact with effectors. In the inactive state, the α-subunit of the G protein is bound to guanosine diphosphate (GDP) and to βγ-subunits. The β- and γ-subunits bind tightly to each other, and the β-subunit also contains a common binding site for α-subunit recognition. A total of 5 distinct β-subunit genes and 12 γ-subunit genes have also been identified. More than 16 distinct genes encode the G protein α-subunits, and there is a splice variant in at least two genes. Approximately 80% of the receptors for neurotransmitters, hormones, and neuromodulators elicit their responses through G proteins. Guanine nucleotide-binding proteins (G proteins) occupy a central position and play a critical role in the transduction of extracellular signals to cellular targets. RIIβ is predominantly expressed in the brain, adipose, and adrenals and may be the principal mediator of cAMP activity in the mammalian CNS since RIβ is widely expressed in the brain but less strongly than RIIβ. ![]() RIβ is expressed mostly in the central nervous system (CNS), whereas tissue distribution studies suggest that RIIα is expressed almost as widely as RIα. RIα, the subunit that is deficient in primary pigmented nodular adrenocortical disease and Carney complex (CNC which is associated with psychological disorders including anxiety), is the most abundant and ubiquitously expressed of the four PKA R subunits. Each R subunit is a separate gene product and has a distinct expression pattern in different tissues. The RIα-containing holoenzymes are activated at a five-fold lower concentration of cAMP than the RIβ-containing holoenzymes. The RIα and RIβ isoforms show 80% and the RIIα and RIIβ isoforms 68% identity. The RI subunits have much greater affinity for cAMP than the RII subunits. ![]()
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