Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP)

Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), specifically the 2',3'-cGAMP isomer, is a pivotal endogenous second messenger and immunotransmitter in the mammalian innate immune system [1.2.1, 1.4.1]. It is synthesized by the enzyme cyclic GMP-AMP synthase (cGAS) upon the detection of double-stranded DNA in the cytosol, which serves as a danger signal for pathogen invasion or cellular damage [1.4.1, 1.6.1]. Once produced, cGAMP binds with high affinity to the Stimulator of Interferon Genes (STING) receptor, triggering a conformational change that activates a signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines [1.4.1, 1.6.2]. Beyond its intracellular role, cGAMP can be transported between cells via gap junctions or specialized transporters, acting as an immunotransmitter to alert neighboring cells [1.2.1, 1.2.4]. In therapeutic development, cGAMP analogs are being investigated as STING agonists to stimulate anti-tumor immunity in various cancers [1.2.2, 1.3.1]. Conversely, inhibitors of cGAMP synthesis are being explored for the treatment of autoimmune and inflammatory diseases characterized by chronic interferon production [1.4.2, 1.5.2]. The regulation of cGAMP levels is also influenced by the extracellular enzyme ENPP1, which degrades cGAMP to attenuate immune signaling, making ENPP1 another key target in the pathway [1.3.1, 1.3.2].

Other names

2',3'-cGAMPCyclic (adenosine monophosphate-guanosine monophosphate)2',3'-cyclic GMP-AMPCyclic AMP-GMPCyclic dinucleotide

Activation of the Stimulator of Interferon Genes (STING) receptor to induce type I interferon and pro-inflammatory cytokine production; inhibition of cyclic GMP-AMP synthase (cGAS) to prevent cGAMP synthesis; inhibition of ENPP1 to prevent cGAMP degradation.