Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs from , and three other protists. All the RhoPDEs (fused with a cytosolic N-terminal YFP tag) can be expressed in oocytes, except the RhoPDE that lacks the retinal-binding lysine residue in the last (8th) transmembrane helix. An N296K mutation of YFP::RhoPDE enabled its expression in oocytes, but this mutant still has no cGMP hydrolysis activity. Among the RhoPDEs tested, RhoPDE, RhoPDE1, 4 and RhoPDE exhibited light-enhanced cGMP hydrolysis activity. Engineering RhoPDE, we obtained two single point mutants, L623F and E657Q, in the C-terminal catalytic domain, which showed ~40 times decreased cGMP hydrolysis activity without affecting the light activation ratio. The molecular characterization and modification will aid in developing ideal light-regulated phosphodiesterase tools in the future.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774190 | PMC |
| http://dx.doi.org/10.3390/biom12010088 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum.
Neurobiol Dis
December 2024
Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy.
Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/- (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice.
View Article and Find Full Text PDFMultimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review.
J Biochem Mol Toxicol
November 2024
Division of Pharmacology, Institute of Pharmaceutical Research, GLA University, Chaumuhan, Mathura, India.
Article Synopsis
- - PDE5 is an enzyme that breaks down cGMP, a molecule crucial for enhancing neural signals and influencing learning and memory processes, and it's found in the brain and in the smooth muscle of the corpus cavernosum.
- - PDE5 inhibitors, which prevent the breakdown of cGMP, can enhance nitric oxide effects, providing anti-inflammatory and neuroprotective benefits, potentially addressing neurodegenerative disorders, which currently lack curative treatments.
- - The review explores how PDE5 inhibitors may act as disease-modifying agents for conditions like Alzheimer's and Parkinson's diseases by simultaneously influencing both cAMP and cGMP pathways, potentially improving neurological functions.
Upregulation of Phosphodiesterase 7A Contributes to Concurrent Pain and Depression via Inhibition of cAMP-PKA-CREB-BDNF Signaling and Neuroinflammation in the Hippocampus of Mice.
Int J Neuropsychopharmacol
October 2024
Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.
Background: Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression.
View Article and Find Full Text PDFPotential of phosphodiesterase 4B inhibitors in the treatment of interstitial lung disease associated with autoimmune diseases.
Clin Exp Rheumatol
August 2024
Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL, USA.
Patients with autoimmune disease-related interstitial lung disease may develop pulmonary fibrosis, which may become progressive. Progressive pulmonary fibrosis (PPF) is associated with poor outcomes. Antifibrotic therapies have shown efficacy as treatments for PPF in patients with autoimmune diseases, but new treatments are needed to slow or halt disease progression.
View Article and Find Full Text PDFResearch progress on phosphodiesterase 4 inhibitors in central nervous system diseases.
Zhejiang Da Xue Xue Bao Yi Xue Ban
June 2024
School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
Phosphodiesterases (PDE) are involved in the regulation of cellular physiological processes and neurological functions, including neuronal plasticity, synapto-genesis, synaptic transmission, memory formation and cognitive functions by catalyzing the hydrolysis of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Many basic and clinical studies have shown that PDE4 inhibitors block or ameliorate the occurrence and development of central nervous system (CNS) diseases by inhibiting cAMP hydrolysis, increasing cAMP content and enhancing its downstream effects. PDE4 inhibitors have long-term potentiation effect, which can enhance phosphorylation of cAMP response element binding protein (CREB) and upregulate expression of memory related Arc genes in hippocampal neurons, thereby improving cognitive impairment and Alzheimer's disease-like symptoms.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!