Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with spared nerve injury neuropathy

Shiers, Stephanie; Elahi, Hajira; Hennen, Stephanie; Price, Theodore J.

doi:10.1016/j.ynpai.2021.100081

Cited by 4 publications

(4 citation statements)

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“…5 The Ca++ combines with calmodulin to activate adenylyl cyclase-1 (AC-1). AC-1 is one of the 10 subtypes of adenylate cyclase and is the predominant type in the ACC ( Shiers et al. 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Toward the unknown: consciousness and pain

Ambron

2023

Neuroscience of Consciousness

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Studies of consciousness are hindered by the complexity of the brain, but it is possible to study the consciousness of a sensation, namely pain. Three systems are necessary to experience pain: the somatosensory system conveys information about an injury to the thalamus where an awareness of the injury but not the painfulness emerges. The thalamus distributes the information to the affective system, which modulates the intensity of the pain, and to the cognitive system that imparts attention to the pain. Imaging of patients in pain and those experiencing placebo and hypnosis-induced analgesia shows that two essential cortical circuits for pain and attention are located within the anterior cingulate cortex. The circuits are activated when a high-frequency input results in the development of a long-term potentiation (LTP) at synapses on the apical dendrites of pyramidal neurons. The LTP acts via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, and an anterior cingulate cortex–specific type-1 adenylate cyclase is necessary for both the LTP and the pain. The apical dendrites form an extensive network such that the input from serious injuries results in the emergence of a local field potential. Using mouse models, I propose experiments designed to test the hypothesis that the local field potential is necessary and sufficient for the consciousness of pain.

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Section: Resultsmentioning

confidence: 99%

Toward the unknown: consciousness and pain

Ambron

2023

Neuroscience of Consciousness

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“…This may be attributed to differences in AC1- or AC8-CaM interactions, since CaM has one mode of interaction with the C1b domain of AC1, whereas it can interact with the N-terminal domain and the C2b domain of AC8. Although we screened and selected for AC1-selective inhibitors, it is possible that AC8 inhibition could be beneficial for anxiety associated with various chronic and inflammatory pain states in humans and rodents (see ( Shiers et al, 2022 ) and references therein). Multiple studies have reported that AC8 knockout mice exhibited reduced anxiety-like behaviors in the elevated plus maze test ( Schaefer et al, 2000 ; Bernabucci & Zhuo, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple studies have reported that AC8 knockout mice exhibited reduced anxiety-like behaviors in the elevated plus maze test ( Schaefer et al, 2000 ; Bernabucci & Zhuo, 2016 ). Furthermore, Shiers et al showed that Adcy8 mRNA expression increased in the anterior cingulate cortex (ACC) in a mouse model of neuropathic pain, although AC8 knockout does not play a role in mechanical hypersensitivity after inflammation ( Wei et al, 2002 ; Shiers et al, 2022 ). This suggests a potential role of AC8 in anxiety-like behaviors.…”

Section: Discussionmentioning

confidence: 99%

Protein-protein interaction-based high throughput screening for adenylyl cyclase 1 inhibitors: Design, implementation, and discovery of a novel chemotype

et al. 2022

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Genetic and preclinical studies have implicated adenylyl cyclase 1 (AC1) as a potential target for the treatment of chronic inflammatory pain. AC1 activity is increased following inflammatory pain stimuli and AC1 knockout mice show a marked reduction in responses to inflammatory pain. Previous drug discovery efforts have centered around the inhibition of AC1 activity in cell-based assays. In the present study, we used an in vitro approach focused on inhibition of the protein-protein interaction (PPI) between Ca2+/calmodulin (CaM) and AC1, an interaction that is required for activation of AC1. We developed a novel fluorescence polarization (FP) assay focused on the PPI between an AC1 peptide and CaM and used this assay to screen over 23,000 compounds for inhibitors of the AC1-CaM PPI. Next, we used a cellular NanoBiT assay to validate 21 FP hits for inhibition of the AC1-CaM PPI in a cellular context with full-length proteins. Based on efficacy, potency, and selectivity for AC1, hits 12, 13, 15, 18, 20, and 21 were prioritized. We then tested these compounds for inhibition of AC1 activity in cyclic AMP (cAMP) accumulation assays, using HEK293 cells stably expressing AC1. Hit 15 contained a dithiophene scaffold and was of particular interest because it shared structural similarities with our recently reported benzamide series of AC1 inhibitors. We next tested a small set of 13 compounds containing the dithiophene scaffold for structure-activity relationship studies. Although many compounds were non-selective, we observed trends for tuning AC1/AC8 selectivity based on heterocycle type and substituents. Having an ethyl on the central thiophene caused the scaffold to be more selective for AC8. Cyclization of the alkyl substituent fused to the thiophene significantly reduced activity and also shifted selectivity toward AC8. Notably, combining the fused cyclohexane-thiophene ring system with a morpholine heterocycle significantly increased potency at both AC1 and AC8. Through designing a novel FP screen and NanoBiT assay, and evaluating hits in cAMP accumulation assays, we have discovered a novel, potent, dithiophene scaffold for inhibition of the AC1- and AC8-CaM PPI. We also report the most potent fully efficacious inhibitor of AC8 activity known to-date.

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“…The sural nerve isn't altered, thus it's safe. The method is known as sparing nerve injury since the two additional nerves (the common fibular or tibial) are segmented (Shiers et al, 2022). Any straining or contact with the sural nerve that has been spared has to be avoided.…”

Section: Sni (Spared Nerve Injury)mentioning

confidence: 99%

Neuropathy; its profile and experimental nerve injury neuropathic pain models: A Review

Kumar

2023

Preprint

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Neuropathy is a terrible disorder that has a wide range of aetiologies. Drug-Induced Neuropathy, which happens whenever a chemical agent damages the peripheral nerve system, has been linked here to iatrogenic creation of some drugs. It is potentially permanent and causes sensory impairments and paresthesia that typically affects the hands, feet, and stockings; motor participation is uncommon. It might appear suddenly or over time, and the long-term outlook varies. The wide range of chronic pain conditions experienced by people has been some of the main obstacles to developing new, more effective medications for the treatment of neuropathic pain. Animal models can be used to examine various neuropathic pain aetiologies and symptoms. Several models investigate the peripheral processes of neuropathic pain, whereas some even investigate the central mechanisms. such as drug induce models like vincristine, cisplatin, bortezomib, or thalidomide, etc., and surgical models like sciatic nerve chronic constriction injury (CCI), sciatic nerve ligation through spinal nerve ligation (SNL), sciatic nerve damage caused by a laser, SNI (spared nerve injury), etc. The more popular animal models relying on peripheral nerve ligatures are explained. In contrast to chronic sciatic nerve contraction, which results in behavioral symptoms of less reliable stressful neuropathies, (SNI) spared nerve injury generates behavioral irregularities which are more feasible over a longer period. This review summarizes the latest methods models as well as clinical ideas concerning this mechanism. Every strongest current information on neuropathy is discussed, along with several popular laboratory models for causing neuropathy.

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Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with spared nerve injury neuropathy

Cited by 4 publications

References 44 publications

Toward the unknown: consciousness and pain

Toward the unknown: consciousness and pain

Protein-protein interaction-based high throughput screening for adenylyl cyclase 1 inhibitors: Design, implementation, and discovery of a novel chemotype

Neuropathy; its profile and experimental nerve injury neuropathic pain models: A Review

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