Transmission of an extracellular signal across the cell membrane is initiated by activation of many types of hormone and neurotransmitter receptors, such as G-protein coupled receptors (GPCRs), and continues through signaling cascades of intracellular enzymes and proteins to produce changes in cellular processes. Cyclic nucleotides, including cyclic AMP (cAMP), cyclic GMP (cGMP) and cyclic ADP-ribose, have been extensively studied as second messengers of intracellular events initiated by activation of GPCRs. cAMP modifies cell function in all eukaryotic cells, principally through the activation of cAMP-dependent protein kinase (PKA), but also through cAMP-gated ion channels and guanine nucleotide exchange factors directly activated by cAMP. Cellular levels of cAMP reflect the balance between the activities of adenylyl cyclase (or adenylate cyclase) and cAMP phosphodiesterases (PDEs). cGMP serves as a second messenger in a manner similar to that observed with cAMP, activating specific cGMP-dependent protein kinases (PKG). In addition to cAMP and cGMP, several cyclic dinucleotides have been shown to act as prokaryotic secondary messengers and as agonists of the innate immune response in hosts. 2',3'-cGAMP is the natural agonist for the STING (STimulator of INterferon Genes) pathway, a eukaryotic pathway for antiviral innate immunity. It is a second messenger produced in mammalian cells by the cytosolic DNA sensor cGAS (cGAMP synthase) to activate innate immune responses by binding to STING and initiating an interferon response.
Signaling through cyclic nucleotide second messengers regulates a wide array of metabolic, physiological, functional processes, making cyclic nucleotides and related enzymes vital targets in research of diseases such as cancer, diabetes and cardiovascular disease. Given its role in disease, we know it is essential to ensure that your target is the right target, in order to translate the basic understanding of cyclic nucleotide signaling into therapeutic treatments. We offer several cyclic nucleotides and cAMP/cGMP analogs as well as a number of enzyme and kinase agonists, antagonists and inhibitors for target identification and validation in research of these second messengers and their associated processes; a selection of these research tools is shown below.
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