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Postulated Physiological and Pathophysiological Roles on Motility
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Hans-Dieter Allescher, Sultan Ahmad
The effect of substance P given intra-arterially in the dog to the small intestine was dependent on the activity state of the gut segment.377 In the ileum, substance P induced contractions at lower concentrations by a neural postganglionic pathway, presumably by release of acetylcholine since the response was blocked by atropine.384 At higher concentrations a TTX- and atropine-insensitive excitatory effect was present.377,384 In contrast, when contractile activity was induced by electrical field stimulation of intrinsic nerves, substance P inhibited it at concentrations of substance P (threshold 10−13 mol) even lower than those causing excitation in the same muscle. This inhibitory effect of substance P could be reduced by atropine or pirenzepine and mimicked by acetylcholine and McNeil A343, an M1-muscarinic agonist. These observations suggest that the inhibitory effect is due in part to the release of acetylcholine acting on M1 receptors and causing an autoinhibition.377 Similar excitatory and inhibitory effects of substance P on basal and stimulated [3H]ACh release were demonstrated in the guinea pig ileum.344,385 This inhibitory effect also was observed in the antroduodenal region of dogs using an NK-3-selective analogue suggesting that this response is mediated via a prejunctional NKB receptor.7
Transmitter Regulation of Mesencephalic Dopamine Cells
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Vincent Seutin, R. Alan North, Steven W. Johnson
It is well known that DA can be released from soma-dendritic regions of midbrain DA neurons.60,61 This release can also be detected electrophysiologically. In a small proportion of cells, a focal stimulation to the surface of the slice evokes a synaptic hyperpolarization that has many of the features of the GABAB synaptic potential.7 However, it is not blocked by 2-hydroxysaclofen. Instead, this synaptic potential is enhanced by cocaine and blocked by sulpiride, which presumably act by blocking DA reuptake and blocking D2 receptors, respectively.7 The ionic mechanism of the synaptic potential is also consistent with that of exogenously applied DA which hyperpolarizes DA cells by increasing the membrane potassium conductance.7,11 The overall physiological significance of this feedback ‘autoinhibition’ remains to be determined.
Melanotropin Mechanisms of Action: Melanosome Movements
Published in Mac E. Hadley, The Melanotropic Peptides, 2018
Mac E. Hadley, Ana Maria de L. Castrucci
Several fragment analogs of MCH have been synthesized and characterized for melanotropic activity: MCH1-14, MSH5-17, and MCH5-14.38 Structure-activity studies have determined that the 5-17 sequence was as active as the native peptide, suggesting that the N-terminal tetrapeptide sequence may be of no importance for receptor activation. The 1-14 sequence was approximately 30 times less active than the native 1-17 sequence, and the central cyclic 5-14 sequence proved to be approximately 300 times less active. One or more residues of the 15-17 sequence are apparently essential for equipotency at the MCH receptor. At higher, unphysiological concentrations, MCH exhibited a self-antagonism, an autoinhibition.39 It was hypothesized that the peptide possessed some intrinsic MSH-like activity and that MCH and MSH might be evolutionarily related (see Sherbrooke et al., Volume II, Chapter 12).
Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor
Published in Xenobiotica, 2019
Bianca M. Liederer, Jonathan Cheong, Kang-Jye Chou, Peter S. Dragovich, Hoa Le, Xiaorong Liang, Justin Ly, Sophie Mukadam, Jason Oeh, Deepak Sampath, Leslie Wang, Susan Wong
The results of the simulations performed in Simcyp® are presented in Figures 7 and 8. Simulations were performed at the preliminary projected clinically efficacious dose using predicted human PK parameters of GNE-617 at steady-state concentrations. As shown in Figure 7, the AUC for S-warfarin (probe substrate for CYP2C9) and rosiglitazone (probe substrate for CYP2C8) were not significantly altered in the presence of GNE-617. The AUC ratio, defined as the AUC of the probe substrate in the presence and absence of predicted human exposures of GNE-617, was less than 2-fold for all simulated healthy human volunteers (n = 80). There was a 5-fold increase in AUC for midazolam (probe substrate for CYP3A4/5) in the presence of GNE-617, suggesting a moderate clinical DDI risk with CYP3A4/5 substrates. As shown in Figure 8, pronounced accumulation of GNE-617 suggestive of autoinhibition was only seen when fmCYP3A was set to 0.9 but not if set to 0.1 or 0.5. AUC96-120 hrs ratios of fmCYP3A 0.1, 0.5 and 0.9 versus 0 were 1.1, 1.8 and 5.8, respectively.
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
PLKs are the master regulators of cell division process. Multiple mechanisms limit the activities of these kinases to short periods during cell cycle in order to prevent prolonged PLK activation-associated genomic instability. Similar to other PLKs, PLK4 also possesses autoinhibition and relief mechanisms which govern the centriole duplication process via regulating PLK4 oligomerization and stability. Trans-autophosphorylation and ubiquitin-mediated degradation are key events in PLK4 regulation. A newly synthesized PLK4 exists in an autoinhibited monomeric state. This intrinsically inactivated state is presumably maintained by L1-mediated autoinhibition that prevents activation loop (AL) phosphorylation. Subsequent homodimerization results in relief of autoinhibition and stimulation of kinase activity. The PB1-PB2 domain mediates this dimerization process, while PB3 displaces L1 away from the AL of kinase domain and mitigates autoinhibition [50]. Binding of STIL to PB3 and L1 regions of PLK4 induces PLK4 activation and trans-autophosphorylation [52]. Following dimerization, PLK4 induces autophosphorylation at multiple sites in a sequential manner. Phosphorylation of AL present in the kinase domain results in increased kinase activity, while phosphorylation of the conserved phosphodegron motif (DSGXXT) is critical for protein degradation. Phosphorylation of the L1 regions further relieves autoinhibition, while that of L2 leads to dimer separation. This sequential autophosphorylation ensures adequate levels of PLK4 are present to elicit the essential events in cell cycle before self-destruction occurs. Moreover, this complex pattern of PLK4 phosphorylation directs either PLK4 activation or suppression depending on the residues modified (Figure 3) [50].