Cyclic GMP (cGMP)

This chapter is related to the aims of Section C(iv) from the 2023 CICM Primary Syllabus, which expects the exam candidate to "explain receptor activity with regard to... second messengers and G proteins". Whereas cyclic AMP is probably the stereotypic secondary messenger molecule with importance primarily to catecholamine inotropes, cyclic GMP is the critical molecule required for smooth muscle relaxation. 

If your home institution gives you access to archive copies of Pharmacological Reviews, the 1987 article by Waldman and Murad is an excellent and highly detailed introduction to this topic. It is, of course, well in excess of what is required for the CICM primary exam, in which this topic has never appeared. A more pragmatic article, which happens to be available for free is Tsai & Kass (2009) - this probably has more exam relevance because the focus is on the role of cGMP in regulating cardiovascular phenomena.

In summary:

  • Cyclic guanosine monophosphate is a cyclic nucleotide secondary messenger
  • It is produced when guanylyl cyclase is activated by nitric oxide, or by a natriuretic peptide
  • It is degraded by phosphodiesterases (some of which also degrade cAMP)
  • Its main downstream target is Protein Kinase G (PKG) 
  • PKG decreases IP3 activity, desensitises myofibrils to calcium, and decreases intracellular calcium availability by several other mechanisms
  • The net effect of cGMP secondary messenger activity is smooth muscle relaxation

Synthesis and characteristics of cGMP

Cyclic guanosine monophosphate is similar to cyclic AMP, with the exception that instead of adenine cGMP has a guanine nucleobase. It is derived from GTP (guanosine triphosphate). There are two major pathways of its synthesis, one via a membrane-bound guanylyl cyclase bound to a natriuretic peptide receptor, and the other a soluble guanylyl cyclase which is activated by nitric oxide. Like cyclic AMP, cGMP is degraded by phosphodiesterases. Some phosphodiesterases only affect cGMP (eg. PDE-5A, the target of sildenafil) whereas others (PDE-2 and PDE-3) can hydrolyse both cAMP and cGMP. 

Cyclic GMP pathway

The attentive reader will have noticed a missed step (omitted to preserve the eye-pleasing relationship of circles) where cGMP seems to become GTP. 

  • Guanylul cyclase makes cGMP from GTP
  • cGMP is degraded by phosphodiesterase into GMP
  • GMP and GTP are ubiquitous and GMP is converted into GTP in several different ways which are not relevant to the discussion of secondary messenger systems, which is why they were omitted here.

cGMP has numerous downstream effects, listed nicely in Tsai & Kass (2009):

From Protein Kinase G activation

  • Smooth muscle relaxation by decreased intracellular calcium availability
  • Negative inotropic effect, by reduction of myofilament calcium responsiveness
  • Promotion of angiogenesis
  •  

From cGNP-gated ion channels

  • mainly unselective cation channels, relevant to the movement of sodium and calcium ions (Kaupp et al, 2002) - these are mainly expressed in retinal and olfactory neuroepithelium and in nephrons (i.e. these channels have no relevance to the cardiovascular system).

From cGMP-modulated phosphodiesterase 

  • cGMP can bind to phosphodiesterases which increases their activity against both cGMP and cAMP, resulting in the inhibition of both secondary messenger systems. 

Clinically relevant effects of cGMP signalling pathways

In short, the relevance of cGMP to cardiovascular physiology and pharmacology is mainly related to its activation by nitric oxide, and the relevance of this is mainly to vascular smooth muscle. The steps of this activity are as follows:

  • Something (anything) activates nitric oxide synthase
  • Nitric oxide (NO) is synthesised
  • NO activates the soluble form of guanylyl cyclase at nanomolar concentrations
  • Guanylyl cyclase produces cGMP
  • cGMP activates Protein Kinase G (PKG)
  • The 1β isoform of PKG phosphorylates the IP3 receptor, inhibiting IP3-mediated release of calcium
  • PKG also phosphorylates and thus inactivates voltage-gated calcium channels.
  • PKG also phosphorylates phospholamban, leading to increased calcium ion uptake into sarcoplasmic reticulum

The net effect of these changes is a decrease in the availability of intracellular calcium, and therefore smooth muscle relaxation.

References

Waldman, S. A., and F. Murad. "Cyclic GMP synthesis and function." Pharmacological Reviews 39.3 (1987): 163-196.

Lincoln, THOMAS M., and TRUDY L. Cornwell. "Intracellular cyclic GMP receptor proteins." The FASEB Journal 7.2 (1993): 328-338.

Tsai, Emily J., and David A. Kass. "Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics."  Pharmacology & therapeutics 122.3 (2009): 216-238.

Kaupp, U. Benjamin, and Reinhard Seifert. "Cyclic nucleotide-gated ion channels." Physiological reviews 82.3 (2002): 769-824.