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Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
To gain a better understanding of second-messenger systems, it is necessary to review first some biochemistry in order to explain the structure of an important, typical second-messenger cyclic AMP (cAMP) and the guanine-derived phosphates. It should be recalled that two of the basic constituents of nucleic acids are the purine compounds adenine and guanine. When attached to the 1ʹ carbon atom of a ribose sugar molecule (Figure 6.10), they become the nucleosides adenosine and guanosine, respectively. When a single phosphate group is attached to the 5ʹ carbon atom of a ribose sugar molecule, these nucleosides become the nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP), respectively. However, another phosphate group can attach to the first phosphate group to give adenosine diphosphate (ADP) and guanosine diphosphate (GDP), respectively. The attachment of a third phosphate group to the second phosphate group, gives adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively.cAMP molecule.
Autonomic Regulation of Myocardial Contractility*
Published in Irving H. Zucker, Joseph P. Gilmore, Reflex Control of the Circulation, 2020
Walter C. Randall, David C. Randall, Jeffrey L. Ardell
Postjunctionally, NE released from sympathetic terminals combines with β-adrenergic receptors in the cell membrane to stimulate adenylate cyclase that catalyzes formation of cyclic AMP (cAMP) from ATP. This reaction is mediated by a stimulatory protein, Gs, and involves hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). At vagal nerve terminals, ACh combines with muscarinic (M) receptors on the effector cell surface. The muscarinic receptor inhibits adenylate cyclase through an inhibitory coupling protein Gi that also catalyzes the hydrolysis of GTP to GDP. The adenylate cyclase system is thus the primary focus of adrenergic-cholinergic interactions. Increased sympathetic input is mediated through elevations in levels of cAMP, and the antagonist effect of vagally released ACh is via inhibition of adenylate cyclase, thereby attenuating a sympathetically induced rise in intracellular cAMP (Levy, 1988).
The endocrine system
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
The most common second messenger activated by the protein/peptide hormones and the catecholamines is cyclic adenosine monophosphate (cAMP). The pathway by which cAMP is formed and alters cellular function is illustrated in Figure 11.1. The process begins when the first messenger binds to its receptor. These receptors are quite large and span the bilayer of phospholipids within the plasma membrane. On the intracellular surface of the membrane, the receptor is associated with a protein called G protein, which serves as a transducer molecule. These proteins are referred to as G proteins because they bind with guanosine nucleotides. G protein acts as an intermediary between the receptor and the second messengers that will alter cellular activity. In an unstimulated cell, the inactive G protein binds guanosine diphosphate (GDP). When the hormone binds to its G protein-associated receptor, the G protein releases GDP, and becomes able to bind with guanosine triphosphate (GTP), which is found in the cytoplasm. Upon binding with the GTP, the now activated G protein loses its affinity for the receptor and increases its affinity for the plasma membrane-embedded enzyme, adenylyl cyclase. In turn, the adenylyl cyclase becomes activated and splits adenosine triphosphate (ATP) to form cAMP. The cAMP molecule serves as the second messenger that carries out the effects of the hormone inside the cell.
Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain
Published in Expert Opinion on Pharmacotherapy, 2022
Qiu Qiu, Joshua CJ Chew, Michael G Irwin
All opioid receptors are inhibitory G-protein coupled receptors (GPCRs). Although the clinical effects can differ, the signaling mechanism of inhibitory GPCRs are the same. When an opioid agonist binds to the receptor, the receptor complex undergoes a conformational change. The α subunit exchanges its bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP). Subsequently, the α-GTP and βγ subunit dissociate and proceed to interact with effector proteins such as adenylate cyclase and modulate ion channels. With inhibitory GPCRs, agonism causes the inhibition of adenylyl cyclase, leading to the reduction in formation of intracellular adenosine monophosphate (cAMP). The βγ subunit activates G protein-coupled inwardly rectifying potassium channels and inhibits voltage gated calcium channels. This results in hyperpolarisation and decreased neurotransmitter release. Agonism also leads to the recruitment of GPCR kinase which phosphorylates the GPCR. The phosphorylated GPCR subsequently binds β-arrestin, and this family of cytosolic proteins has been implicated in causing respiratory depression, tolerance and constipation. Phosporylated GPCRs can be recycled to the cell membrane or undergo lysosomal degradation [12–15] (Figure 1). Reduced available receptors via this mechanism is how the receptor is negatively regulated, and leads to decreased sensitivity and tolerance [16].
Fixed-combination topical anti-hypertensive ophthalmic agents
Published in Expert Opinion on Pharmacotherapy, 2020
Lindsay Machen, Reza Razeghinejad, Jonathan S. Myers
Netarsudil is a rho kinase inhibitor and is postulated to lower IOP by increasing outflow through the trabecular meshwork, decreasing production of aqueous humor, and decreasing episcleral venous pressure through hypothesized vasodilatory mechanisms [114]. Rho kinase inhibitors work by binding to guanosine triphosphate, the activated form, and become inactivated when bound to guanosine diphosphate [115]. In addition to its activity as a rho kinase inhibitor, netarsudil has the unique capacity to serve as a norepinephrine transporter inhibitor [115]. Side effects appear limited in major studies with conjunctival hyperemia, subconjunctival hemorrhage, and corneal verticillata representing the greatest noted side effects [116]. The conjunctival hyperemia is postulated to be secondary to smooth muscle relaxation and vasodilation of the conjunctiva [117]. In phase III trials, netarsudil was found to be non-inferior to timolol in patients with baseline IOP <25 mmHg suggesting utility of netarsudil as an adjuvant agent for patients with lower initiating pressures [115]. ROCKET-4 was an expansion study inspired by the failure of the ROCKET-1 and 2 studies to prove non-inferiority when the treated population had a baseline IOP greater than 27 mmHg. ROCKET-4 looked at pre-specified secondary endpoints in patients with baseline IOP <27 mmHg and <30 mmHg and demonstrated non-inferiority to timolol for all baseline IOPs assessed [118].
Recent advances in precision medicine for the treatment of anaplastic thyroid cancer
Published in Expert Review of Precision Medicine and Drug Development, 2019
Silvia Martina Ferrari, Poupak Fallahi, Concettina La Motta, Giusy Elia, Francesca Ragusa, Ilaria Ruffilli, Armando Patrizio, Enke Baldini, Salvatore Ulisse, Alessandro Antonelli
H-, K-, and N-RAS genes encode for GTPase proteins present on the inner cell membrane and activate the MAPK and PI3K/Akt/mTOR pathways, influencing cell proliferation, survival, and differentiation [33]. When RAS proteins bind to guanosine diphosphate (GDP), they are inactive, while when bind to guanosine triphosphate (GTP), they are active and hydrolyze GTP to GDP [33]. RAS point mutations are present in various malignancies, as head and neck cancers [33], and RAS mutations associated with TCs involve codons HRAS, NRAS (in 61 codon), and KRAS (in codon 13/12) [34]. Point mutations within RAS genes are found in approximately 15% PTCs, 40% of FTCs, and 50% of ATCs. Mutant RAS are correlated to a poor prognosis and more aggressive behavior of ATC [35,36]. Some Authors suggest a more extensive genetic analysis to predict TC outcome, since a more aggressive clinical course is present in those patients with combination of mutations, as telomerase reverse transcriptase promoter (TERTp) and BRAFV600E, or TERTp and RAS [37,38].