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Biochemistry, Cyclic GMP

Editor: Muhammad F. Hashmi Updated: 9/26/2022 5:56:05 PM


Guanosine 3’,5’-cyclic monophosphate (cyclic GMP or cGMP) is a second messenger molecule that modulates various downstream effects, including vasodilation, retinal phototransduction, calcium homeostasis, and neurotransmission. cGMP mediates these effects via activation and alteration of specific ion channels, association with cGMP-dependent protein kinases, and interaction with phosphodiesterases (PDEs). In this review, we will discuss the activation and regulation of cGMP, its downstream effects, and potential clinical significance.


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Guanylate cyclase (GC) is a lyase enzyme that catalyzes the synthesis of cGMP. Guanylate cyclase is usually interacting with the G protein cascade, which is activated by low levels of calcium levels. In response to calcium, GC converts Guanosine-5'-triphosphate (GTP) into cGMP.[1]

Issues of Concern

cGMP is involved with a diversity of physiological processes in many cell types in the cardiovascular system. Dysfunction in cGMP signaling at most steps can lead to many cardiovascular diseases.[2] Overactivated cGMP is also associated with enterotoxigenic Escherichia coli, leading to decreased resorption of sodium chloride and water in the gut.[3]

Cellular Level

Cyclic nucleotide-gated ion (CNG) channels are ion channels that become directly activated via the binding of cyclic nucleotides. CNG channels are nonselective cation channels that mainly promote a current of sodium and calcium ions, and have been best characterized in retinal photoreceptors. However, researchers have also identified them in olfactory sensory neurons and the pineal gland. Rod and cone CNG channels are selective for cGMP, while cAMP can also activate others.[4] Furthermore, cGMP is associated with atrial natriuretic peptide, where it aides in vasodilation and decreased sodium reabsorption at the renal collecting tubules.[5]

Molecular Level

cGMP levels get balanced by the opposing actions of guanylate cyclase, which synthesizes cGMP from GTP, and phosphodiesterases (PDEs), which convert cGMP to 5’-GMP, ending its activity. Nitric oxide (NO) binds to soluble guanylate cyclase (sGC) and greatly increases its catalytic activity, increasing the conversion of GTP to cGMP. The other mechanism of cGMP conversion is receptor-mediated, typically activated through natriuretic peptide (NP) ligand binding to particulate guanylate cyclase (pGC).[6] cGMP is the only second messenger activated by gas.[2]

cGMP mediates its effects through three main pathways. cGMP-dependent serine/threonine protein kinases (PKGs) are enzymes primarily activated through ligand binding by cGMP. There are two identified subclasses, PKGI and PKGII, which differ in both tissue distribution and targets of phosphorylation. cGMP also activates protein kinase A (PKA), though it is a weaker agonist than cAMP.[7]

The PDE superfamily consists of 11 members differentiated by cAMP/cGMP substrate specificity, kinetics, activation, and inhibition. cGMP is the sole substrate of PDEs 5, 6, and 9, and is a dual substrate (with cAMP) of PDEs 1, 2, 3, 10, and 11. The dual-specificity of PDE enzymes allows cGMP to effect changes through regulation of cAMP levels as well. By binding to PDE, cGMP can block sites that would normally catalyze cAMP conversion to AMP, resulting in elevated cAMP levels and the downstream effects that this mediates.[8]


NO upregulation of intracellular cGMP has been tied to many effects, mainly mediated by PKGI, including relaxation of GI and vascular smooth muscle, inhibition of platelet aggregation, improvement in cognitive function, and cardioprotection (both hypertrophy and reperfusion injury).[6] PKGI likely modulates smooth muscle function in the gut and vasculature. Mice lacking this protein demonstrated markedly slowed gut motility and elevated blood pressure (hypothesized due to lack of response to NO).[7] Further, PKGI likely modulates neuronal plasticity, erectile function, lower urinary tract function, and endothelial permeability.[6] Additional PKG-mediated functions may include decreasing intracellular calcium levels, regulation of bone metabolism (osteoclast activity), alteration of renal absorption, production of melanocytes in response to UV radiation, and reducing cGMP levels through activation of PDE.[7]

cGMP direct ligand binding to CNG channels is required to open and promote maximal current flow through the channels fully. In photoreceptors and olfactory sensory neurons, cGMP amplification of light stimulation contributes to high visual and olfactory discrimination in humans. cGMP and CNG channels are also involved in calcium homeostasis – low intracellular calcium levels can activate GC activating proteins, leading to increased cGMP and calcium influx through open CNG channels. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, a subset of CNG channels, can be activated by cGMP, although mainly regulated by cAMP. Found mostly in the heart and brain, they often act as pacemaker channels, establishing rhythmically coordinated cardiologic (heartbeat) and neurologic (e.g., movement) activity.[4]

The PDE superfamily expresses heterogeneously throughout the body, and members with an affinity for cGMP will merit brief mention here.[8]

  • PDE1 is mainly present in neurons and appears to mediate brain function and activity through synaptic modulation.
  • PDE2 appears to mediate vascular changes and function.
  • PDE3 may be required for functional meiosis in oocytes and has implications in insulin sensitivity and metabolic activity.
  • PDE5 helps regulate vasomotor tone and blood pressure and has been a primary target of pharmacologic therapies to treat hypertension and erectile dysfunction.
  • PDE6 has been identified as the key phosphodiesterase involved in visual transduction and localizes to the retina.
  • PDE9 is widely expressed throughout the brain and may modulate behavior and learning.
  • PDE10 has also been associated with brain activity and may play a role in neurodegenerative diseases such as Huntington disease.
  • PDE11, though poorly characterized, is highly expressed in prostate and testicular cells and may play a role in reproductive function.


Most cGMP action on vascular function gets mediated through its activation of PKGs balanced by the inactivating PDEs. The effects of cGMP on vascular proliferation are unclear, with studies suggesting both pro and anti-proliferative effects depending on activation (pGC vs. sGC), location, and quantity of intracellular cGMP. cGMP has different, but complementary, effects on inflammatory modulators depending on the activating source. NP induction of pGC appears to reduce both immune cell activation and chemokine release, while NO stimulation of sGC inhibits P-selectin expression, reducing both leukocyte recruitment and thrombosis.[9]

Metabolic homeostasis is another potential area of interest for cGMP research. Generally, cGMP induces positive changes in energy expenditure. In brown adipose tissue where NO induces cGMP, it increases the quantity, size, and activity of mitochondria. Thus it serves to increase energy expenditure in the brown fat cells. cGMP may also induce the browning of white adipose cells and exert similar effects on mitochondria in other cells throughout the body. cGMP potentially improves insulin sensitivity in white adipose cells, regulates glucagon release in the endocrine pancreas, exerts antioxidant and anti-inflammatory effects in the liver, and regulates food and water intake through interactions in the hypothalamus.[10]

cGMP also plays a role in neurological function, most notably regarding synaptic plasticity and memory formation and retrieval. In hippocampal synapses, stimulation of postsynaptic NMDA-receptors can lead to the release of NO into the synaptic cleft, with subsequent binding to the presynaptic neuron and production of cGMP. cGMP appears to increase the presynaptic neuron activity of PKGI, which enhances long-term potentiation (LTP) of the synapse. Supporting this finding, direct injection of cGMP into presynaptic neurons enhances LTP, while injection of a PKG inhibitor blocks LTP. Overall, cGMP may help to facilitate both memory formation and retrieval through its effects on LTP in the hippocampus.[11]

cGMP activity has also shown links to synaptic changes in other brain regions. In the amygdala, cGMP-mediated activity may aid in the LTP of fear-associated memory formation. Conversely, in Purkinje cells of the cerebellum, cGMP has been implicated in synaptic long-term depression (LTD), which underlies motor learning. Less understood are the effects of cGMP on other brain regions. cGMP may mediate cognition, psychosis, depression, and neurodegeneration, likely through PDE activity. Through presynaptic and postsynaptic modulations, as well as effects on neuronal gene expression, cGMP potentially modulates multiple behavioral and learning functions in the CNS.[11]


Measuring urinary cGMP might prove to be a diagnostic tool for kidney function. When examining the kidney, iodine-based radiocontrast agents are used for angiographic procedures. The use of such agents has drawn criticism for the potential risk of contrast-induced nephropathy (CIN). New biomarkers are under investigation to protect patients from this risk. Renal functions influence cGMP concentration in the urine, so studies have been done investigating the use of cGMP as an additional biomarker for renal function to predict major renal events. Research has found that urine cGMP/creatinine ratio greater than or equal to 120 micromoles/millimole before receiving contrast medium is an encouraging biomarker for dialysis along with all-cause mortality 90 days after contrast medium exposure in patients with preexisting diabetes or renal impairments.[12][13]

Phosphorylated-vasodilator-stimulated phosphoprotein (P-VASP) is the established marker for physiological cyclic guanosine monophosphate (cGMP) signaling; this is because cGMP-dependent kinases primarily phosphorylate VASP.[14]


Various systems can regulate cGMP signaling, which leads to vascular smooth muscle (VSM) relaxation in pulmonary arteries. In VSM, cGMP activates type 1 and 2 PKGs. PKG activation promotes calcium-gated potassium channel openings causing relaxation and hyperpolarization. PKG also activates sarcoplasmic and endoplasmic calcium ATPase pump on the sarcoplasmic reticulum (SR), leading to calcium getting pumped into the SR. As calcium fills, SR extracellular calcium is low. The cumulation of these events means PKG signaling leads to decreased intracellular calcium, thus smooth muscle relaxation. PKG also inhibits Rho-kinase. Rho-kinase inhibits myosin light chain phosphatase. Thus, inhibiting Rho-kinase leads to VSM relaxation.

Based on this signaling model, different signaling nodes might lead to pulmonary hypertension, the opposite of pulmonary relaxation. Free radicals can inhibit the binding of NO to sGC, preventing the production of cGMP, thus leading to PKG not causing relaxation. PDE5 can also degrade cGMP.[15]

Clinical Significance

Drug targets for cGMP include GC stimulation and PDE inhibition, both of which increase intracellular levels of cGMP in targeted cells. sGC stimulators are being studied as a potential therapy to treat pulmonary hypertension, due to their ability to increase the synthesis of cGMP even in the absence of NO. Although better known for its ability to treat erectile dysfunction, PDE5 inhibitor sildenafil is being studied for cardioprotective effects. Elevation of myocardial cGMP is associated with improved pulmonary vascular tone and right ventricular function in diastolic heart failure.[16]

Therapies targeting cGMP levels to address visceral pain have demonstrated promising results. In irritable bowel syndrome with constipation (IBS-C), abdominal pain and discomfort are a significant factor in patient quality of life. Guanylate cyclase agonists appear to reduce visceral pain by reducing the hypersensitivity of chronically stimulated nociceptors, by raising extracellular cGMP in the colon.[17]

Through activation of PKG1, targeting cGMP levels may be an effective treatment of kidney disease. PDE5 inhibitors have demonstrated improvement in kidney function, specifically respective to inhibition of renal fibrosis, countering thrombosis through regulation of platelet aggregation, and antitumorigenic properties via promoting apoptosis of tumor cells and inhibiting tumor cell survival signals.[18]

Although associated with many positive outcomes, increased cGMP levels may also have a cytotoxic effect in some instances. In models of retinal dystrophy, elevated cGMP levels correlate with accelerated retinal degeneration. Uncontrolled calcium influx through constitutively open CNG channels, coupled with overactivation of PKGI, may be partially responsible for retinal cell death.[19]

Hydralazine is a medication commonly used to treat severe hypertension and heart failure. It works by increasing the activity of cGMP, leading to smooth muscle relaxation.[20] Other medications used to treat hypertension that utilizes the cGMP pathway are nitroprusside and other nitrates.[21][22]



Kobiałka M,Gorczyca WA, Particulate guanylyl cyclases: multiple mechanisms of activation. Acta biochimica Polonica. 2000     [PubMed PMID: 11310956]

Level 3 (low-level) evidence


Tsai EJ,Kass DA, Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacology & therapeutics. 2009 Jun     [PubMed PMID: 19306895]

Level 3 (low-level) evidence


Zhu Y,Luo Q,Davis SM,Westra C,Vickers TJ,Fleckenstein JM, Molecular Determinants of Enterotoxigenic Escherichia coli Heat-Stable Toxin Secretion and Delivery. Infection and immunity. 2018 Nov;     [PubMed PMID: 30126899]


Kaupp UB,Seifert R, Cyclic nucleotide-gated ion channels. Physiological reviews. 2002 Jul;     [PubMed PMID: 12087135]

Level 3 (low-level) evidence


Cannone V,Cabassi A,Volpi R,Burnett JC, Atrial Natriuretic Peptide: A Molecular Target of Novel Therapeutic Approaches to Cardio-Metabolic Disease. International journal of molecular sciences. 2019 Jul 2;     [PubMed PMID: 31269783]


Francis SH,Busch JL,Corbin JD,Sibley D, cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacological reviews. 2010 Sep;     [PubMed PMID: 20716671]

Level 3 (low-level) evidence


Francis SH,Corbin JD, Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Critical reviews in clinical laboratory sciences. 1999 Aug;     [PubMed PMID: 10486703]

Level 3 (low-level) evidence


Lugnier C, Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacology     [PubMed PMID: 16102838]

Level 3 (low-level) evidence


Kemp-Harper B,Schmidt HH, cGMP in the vasculature. Handbook of experimental pharmacology. 2009;     [PubMed PMID: 19089340]

Level 3 (low-level) evidence


Pfeifer A,Kili? A,Hoffmann LS, Regulation of metabolism by cGMP. Pharmacology     [PubMed PMID: 23756133]

Level 3 (low-level) evidence


Kleppisch T,Feil R, cGMP signalling in the mammalian brain: role in synaptic plasticity and behaviour. Handbook of experimental pharmacology. 2009;     [PubMed PMID: 19089345]

Level 3 (low-level) evidence


Chaykovska L,Heunisch F,von Einem G,Hocher CF,Tsuprykov O,Pavkovic M,Sandner P,Kretschmer A,Chu C,Elitok S,Stasch JP,Hocher B, Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium. PloS one. 2018     [PubMed PMID: 29649334]


Mohammed NM,Mahfouz A,Achkar K,Rafie IM,Hajar R, Contrast-induced Nephropathy. Heart views : the official journal of the Gulf Heart Association. 2013 Jul     [PubMed PMID: 24696755]


Liguori I,Russo G,Curcio F,Bulli G,Aran L,Della-Morte D,Gargiulo G,Testa G,Cacciatore F,Bonaduce D,Abete P, Oxidative stress, aging, and diseases. Clinical interventions in aging. 2018     [PubMed PMID: 29731617]


Patel D,Lakhkar A,Wolin MS, Redox Mechanisms Influencing cGMP Signaling in Pulmonary Vascular Physiology and Pathophysiology. Advances in experimental medicine and biology. 2017     [PubMed PMID: 29047089]

Level 3 (low-level) evidence


Schlossmann J,Schinner E, cGMP becomes a drug target. Naunyn-Schmiedeberg's archives of pharmacology. 2012 Mar;     [PubMed PMID: 22297800]

Level 3 (low-level) evidence


Hannig G,Tchernychev B,Kurtz CB,Bryant AP,Currie MG,Silos-Santiago I, Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Frontiers in molecular neuroscience. 2014;     [PubMed PMID: 24795564]


Shen K,Johnson DW,Gobe GC, The role of cGMP and its signaling pathways in kidney disease. American journal of physiology. Renal physiology. 2016 Oct 1;     [PubMed PMID: 27413196]


Wang T,Tsang SH,Chen J, Two pathways of rod photoreceptor cell death induced by elevated cGMP. Human molecular genetics. 2017 Jun 15;     [PubMed PMID: 28379353]


Dulce RA,Yiginer O,Gonzalez DR,Goss G,Feng N,Zheng M,Hare JM, Hydralazine and organic nitrates restore impaired excitation-contraction coupling by reducing calcium leak associated with nitroso-redox imbalance. The Journal of biological chemistry. 2013 Mar 1;     [PubMed PMID: 23319593]

Level 3 (low-level) evidence


Zhao Y,Vanhoutte PM,Leung SW, Vascular nitric oxide: Beyond eNOS. Journal of pharmacological sciences. 2015 Oct;     [PubMed PMID: 26499181]


Medina P,Segarra G,Martínez-León JB,Vila JM,Otero E,Lluch S, Relaxation and cGMP formation in response to sildenafil and sodium nitroprusside in saphenous veins from normotensive and hypertensive patients. American journal of hypertension. 2002 Sep;     [PubMed PMID: 12219875]