Cited by 161Neuroscience and Neuropharmacology ResearchPhosphodiesterase function and regulationMemory and Neural Mechanisms

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cGMP Signalling in the Mammalian Brain: Role in Synaptic Plasticity and Behaviour

Kleppisch, Thomas, Feil, Robert·2009·Handbook of Experimental Pharmacology

DOI 10.1007/978-3-540-68964-5_24

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Abstract

The second messenger cyclic guanosine 3',5'-monophosphate (cGMP) plays a crucial role in the control of cardiovascular and gastrointestinal homeostastis, but its effects on neuronal functions are less established. This review summarizes recent biochemical and functional data on the role of the cGMP signalling pathway in the mammalian brain, with a focus on the regulation of synaptic plasticity, learning, and other complex behaviours. Expression profiling, along with pharmacological and genetic manipulations, indicates important functions of nitric oxide (NO)-sensitive soluble guanylyl cyclases (sGCs), cGMP-dependent protein kinases (cGKs), and cGMP-regulated phosphodiesterases (PDEs) as generators, effectors, and modulators of cGMP signals in the brain, respectively. In addition, neuronal cGMP signalling can be transmitted through cyclic nucleotide-gated (CNG) or hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. The canonical NO/sGC/cGMP/cGK pathway modulates long-term changes of synaptic activity in the hippocampus, amygdala, cerebellum, and other brain regions, and contributes to distinct forms of learning and memory, such as fear conditioning, motor adaptation, and object recognition. Behavioural studies indicate that cGMP signalling is also involved in anxiety, addiction, and the pathogenesis of depression and schizophrenia. At the molecular level, different cGK isoforms appear to mediate effects of cGMP on presynaptic transmitter release and postsynaptic functions. The cGKs have been suggested to modulate cytoskeletal organization, vesicle and AMPA receptor trafficking, and gene expression via phosphorylation of various substrates including VASP, RhoA, RGS2, hSERT, GluR1, G-substrate, and DARPP-32. These and other components of the cGMP signalling cascade may be attractive new targets for the treatment of cognitive impairment, drug abuse, and psychiatric disorders.

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See all 161

Authors: Kleppisch, T., & Feil, R.
Affiliations: Technical University of Munich (DE)
University of Tübingen (DE)
Corresponding author: Kleppisch, Thomas
ORCID: Feil, Robert
Venue: Handbook of Experimental Pharmacology
Publisher: Springer Berlin Heidelberg
Published: 2009
Issue: 191
Pages: 549-579
ISSN: 0171-2004 (ISSN-L)
DOI: 10.1007/978-3-540-68964-5_24
OpenAlex: W190813598
Cited by: 161
References: 222
Citations by year: 2026: 4 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 9 · 2020: 2 · 2019: 12 · 2018: 9 · 2017: 13 · 2016: 7 · 2015: 3 · 2014: 13 · 2013: 12 · 2012: 20
FWCI: 15.46
Type: book chapter
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Handbook of experimental pharmacology (publishedVersion)
PubMed (publishedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords: cGMP signaling, soluble guanylate cyclase, cGMP-dependent protein kinase, phosphodiesterase, nitric oxide, cyclic nucleotide-gated channels, HCN channels, synaptic plasticity, learning and memory, fear conditioning, anxiety, addiction, depression, schizophrenia, AMPA receptor trafficking, vesicle release, cytoskeletal organization, drug abuse, cognitive impairment, mental illness
MeSH terms: Animals, Brain, Gene Expression Regulation, Cyclic GMP, Humans, Synaptic Transmission, Neuronal Plasticity, Nitric Oxide, Signal Transduction

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cGMP Signalling in the Mammalian Brain: Role in Synaptic Plasticity and Behaviour

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