Intestinal Chloride Secretion: Cyclic Amp and Ca2+ Interactions
T. S. Gaginella in Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Shortly after the discovery of cAMP in 1958, it was shown that cAMP synthesis resulted from the action of an enzyme, adenylylcyclase (AC), generating cAMP and PPi from ATP, and that this reaction represented the most influential step in the control of intracellular concentrations of the second messenger cAMP. The cyclic nucleotide, in turn, activates several target molecules, primarily cyclic AMP-dependent protein kinases, to control such diverse phenomena, as metabolism, ion transport, gene transcription, and memory. The mammalian AC, with molecular mass approximately 110-180 kDa,237 has been grouped into several types, according to localization and activity regulation.238-240 Certain enzymes are broadly expressed, while others (type III) are very restricted in their distribution. Type I enzymes, activated by calmodulin (CaM), are primarily found in brain,241,242 while those belonging to types II, VII, and VIII have been found in brain and lung.237,239,243,244 Type III enzymes have been prevalently described in olfactory tissues,239,245 and the smaller type IV is predominant in testicular tissue.246 Types V and VI are found in small intestine, pancreas, liver, lung, brain, heart, kidney, etc.237 The enzyme structure shows numerous transmembrane spans and displays similarities to the various ion channels and transporters, suggesting a potential transport role for this enzyme.238
Mechanical Stress and Bone Remodeling
Wilson Harvey, Alan Bennett in Prostaglandins in Bone Resorption, 2020
In 1969 Gianelly6 reported that local injection of parathormone (PTH) increased orthodontic tooth movement. Although this is a predictable phenomenon in the light of PTH action on bone remodeling, it helped to focus attention on the role of local mediators of bone resorption in tooth movement. With the knowledge that cyclic nucleotides were important “second messengers” in the response of bone cells to hormones,7-8 it was not long before changes in cAMP concentrations in mechanically stressed bone were investigated. Davidovitch and Shanfeld9 found that cAMP levels were transiently decreased and then persistently elevated in both the tension and pressure areas of alveolar bone. They concluded that mechanical forces acted as the “first messenger” activating bone formation and resorption via the cyclic nucleotide system. A role for cyclic nucleotides was supported by evidence from tissue culture studies by Rodan et al.10 where application of mechanical stress to embryonic chick long bones resulted in a rapid decrease in intracellular cAMP and cGMP.
Cyclic Nucleotides
Enrique Pimentel in Handbook of Growth Factors, 2017
Cyclic nucleotides are purine derivative compounds that have a key role as second messengers in the mechanism of action of externally signaling agents including hormones, growth factors, regulatory peptides, and neurotransmitters. Two cyclic nucleotides, cyclic adenosine 3’,5’-monophosphate (cyclic AMP or cAMP) and cyclic guanine 3’5’-monophosphate (cyclic GMP or cGMP), are involved in such functions, but the first of them, cAMP, is considered to be the most important cyclic nucleotide second messenger in mammalian cells.1-6 The possible role of a third cyclic nucleotide, cyclic cytidine 3’,5’-monophosphate (cCMP), in the regulation of cellular functions by external stimuli is controversial.7
An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases
Published in Expert Opinion on Drug Discovery, 2021
Si Chen, Chen Yan
Increasing evidence has indicated the existence of multiple functionally distinct ‘pools’ of cyclic nucleotides. For example, catecholamines, prostaglandin 2 (PGE2), and adenosine are all able to elevate cAMP elevation in cardiomyocytes (CMs). cAMP generation through β-adrenergic receptor (β-AR) activation by catecholamine stimulates profound CM contraction, while cAMP elevation by PGE2 has a limited role in CM contractility [4]. Chronic activation of β1-AR-derived cAMP signaling elicits detrimental effects such as promoting CM hypertrophy and apoptosis [5,6], while cAMP signaling through activation of adenosine receptors is protective [7,8]. In addition, cAMP produced by adenylyl cyclase 5 (AC5) and AC6 have different cardiac effects: AC5-derived cAMP is detrimental [9,10], whereas AC6-derived cAMP is protective in pathological cardiac remodeling [11,12]. Moreover, modulation of distinct cyclic nucleotide signaling pathways via inhibition of different PDEs elicit distinct effects on CM viability: PDE1 inhibition promotes CM survival [13,14]; PDE3 inhibition promotes CM death [15]; and PDE4 inhibition has no significant effect on CM viability [15]. These differences might be due to different PDEs coupling to distinct cyclic nucleotide-dependent signalosomes. Although most studies have shown negative inotropic [16–20] and cardioprotective effects [21,22] of cGMP in the heart, cGMP from two different sources may have different mechanisms of action [23]. These lines of evidence indicate that cyclic nucleotide signaling events arising from different origins have distinct/unique or even opposing biological functions.
Cell signal transduction: hormones, neurotransmitters and therapeutic drugs relate to purine nucleotide structure
Published in Journal of Receptors and Signal Transduction, 2018
W. R. Williams
Nucleotides are ideal as regulatory compounds, as they exist in syn and anti conformations, cyclized and dephosphorylated forms. The cyclic nucleotide form participates in a ligand-activated, phosphodiesterase-regulated, cross-talk signaling network [44]. The results presented here provide some insight into ligand directed effects on nucleotide structure. The potential of a ligand to promote conformational change of a nucleotide structure, by displacement of nucleotide or a component group from a receptor protein, is evident within the paired structures used in this study as molecular similarity. Ligand structures regulating Gs and Gi alpha subunits relate to the nucleotide cyclization process. Agonist and antagonist structures differentially alter the space-filling structure of nucleotides. Neurotransmitters may competitively replace a nucleotide structure, or part structure, with a more minimal form whereas antagonists provide a replacement structure that is more similar in size and shape. Ligands specific to the different voltage-gated channel classes relate to different components within the nucleotide structure. Relative molecular similarity within nucleotide and ligand structures of LGIC receptor classes identifies the potential for receptor cross-talk.
An evaluation of roflumilast and PDE4 inhibitors with a focus on the treatment of asthma
Published in Expert Opinion on Pharmacotherapy, 2019
Dhuha Al-Sajee, Xuanzhi Yin, Gail M. Gauvreau
The phosphodiesterase superfamily is comprised of 11 enzyme families known as metalophosphohydrolases [25]. This group hydrolyzes cyclic-3,5-adenosine monophosphate (cAMP) and cyclic-3,5-guanosine monophosphate (cGMP) leading to their inactivation in airways and other tissues [26]. cAMP and cGMP play a key role in the regulation of cell activity; in the airways, these nucleotides regulate the smooth muscle tone, mediator secretion and activation of inflammatory cells. The intracellular concentration of cyclic nucleotides is determined by stimulation of surface receptors and intracellular breakdown of cyclic nucleotides by phosphodiesterases [27]. In general, PDE members are ubiquitously expressed in other body tissues and therefore play a critical role in a wide range of biological processed related to immune cells as neutrophils, macrophages, monocytes and matrix cells such as smooth muscle cells [28–30].
Related Knowledge Centers
- Cyclic Adenosine Monophosphate
- Cyclic Guanosine Monophosphate
- Ligand
- Nucleobase
- Nucleotide
- Phosphate
- Protein
- Second Messenger System
- Sugar
- Hydroxy Group