zed below were obtained in collaborative studies: Recent studies have shown that ACh plays an important role in mediating airway inflammation in chronic obstructive pulmonary disease (COPD). To determine which mAChR subtypes are involved in this activity, M1, M2, and M3 mAChR KO mice and WT control mice were exposed to cigarette smoke for several days. Mouse phenotyping studies indicated that the M3 mAChR has a pro-inflammatory role in cigarette smoke-induced neutrophilia and cytokine release, whereas the M1 and M3 mAChRs exert anti-inflammatory effects in this animal model. These findings should be of interest for the development of novel muscarinic drugs useful for the treatment of COPD. (Kistemaker LE, et al. Muscarinic receptor subtype-specific effects on cigarette smoke-induced inflammation in mice. Eur Respir J 42, 1677-88, 2013) The M3 mAChR contributes to bronchial asthma by mediating bronchoconstriction. Recent work suggests that bronchoconstriction can regulate airway remodeling. Using receptor KO mice as a tool, we tested the hypothesis that M3 mAChR activity contributes to allergen-induced remodeling. In wild-type mice, allergen (ovalbumin) exposure induced goblet cell metaplasia, airway smooth muscle thickening, pulmonary vascular smooth muscle remodeling, and deposition of collagen I and fibronectin in the airway wall. These effects were absent or markedly reduced in M3 receptor-deficient mice. In addition, airway smooth muscle and pulmonary vascular smooth muscle mass was clearly reduced in mice lacking M3 receptors. These data indicate that ACh contributes to allergen-induced remodeling and smooth muscle mass via M3 mAChR activity. (Kistemaker LE, et al. Muscarinic M3 receptors contribute to allergen-induced airway remodeling in mice. Am J Respir Cell Mol Biol 50, 690-8, 2014) Accumulating evidence suggests that drugs that are able to selectively stimulate central M4 mAChRs may prove useful for the treatment of schizophrenia. Thus, the recent development of VU0152100, a centrally active, highly selective M4 receptor positive allosteric modulator (PAM), represents a major breakthrough in the field. Studies with M4 receptor KO mice demonstrated that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in an M4 receptor-dependent fashion. VU0152100 also blocked amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex, without causing adverse motor side effects. In vivo microdialysis studies showed that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in distinct regions of the brain. These data strongly suggest that VU0152100 is endowed with potent antipsychotic activity. Selective M4 receptor PAMs may become useful as novel therapeutic agents for the treatment of schizophrenia and related psychiatric disorders. (Byun NE, et al. Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100. Neuropsychopharmacology 39, 1578-93, 2014) The M3 mAChR is expressed in endothelium-intact ophthalmic arteries as well as in ophthalmic arteries in which the endothelium has been removed. ACh concentration-dependently dilated ophthalmic arteries with intact endothelium from wild-type mice, but not from M3 receptor KO mice. In endothelium-removed ophthalmic arteries from wild-type mice, acetylcholine and carbachol treatment led to concentration-dependent vasoconstriction. This effect was virtually abolished in preparations from mice lacking M3 receptors. These findings indicate that the M3 receptor subtype mediates cholinergic endothelium-dependent vasodilation and endothelium-independent vasoconstriction in murine ophthalmic arteries. Thus, the M3 receptor may represent a potential pharmacologic target to modulate blood flow in diseases associated with disturbances of ocular perfusion, such as diabetic retinopathy, age-dependent macular degeneration, or glaucoma. (Gericke A, et al. Role of the M3 muscarinic acetylcholine receptor subtype in murine ophthalmic arteries after endothelial removal. Invest Ophthalmol Vis Sci 55, 625-31, 2014) Previous studies have shown that mAChRs mediate inhibition of pain transmission at the spinal level. However, it remains unclear which mAChR subtypes are involved in modulating excitatory synaptic input from primary afferents. To address this issue, we examined excitatory postsynaptic currents of dorsal horn neurons evoked by dorsal root stimulation in spinal cord slices from wild-type and different mAChR KO strains. These studies showed that activation of presynaptic M2 and M4 receptors reduces glutamate release from primary afferents, whereas activation of M5 receptors either directly increases primary afferent input or inhibits it by indirectly stimulating group II/III mGluRs. These new findings advance our knowledge of how mAChRs control nociceptive signaling and should facilitate the development of novel classes of analgesic drugs targeting distinct mAChR subtypes. (Chen SR, et al. Differential regulation of primary afferent input to spinal cord by muscarinic receptor subtypes delineated using knockout mice. J Biol Chem 289, 14321330, 2014) Reactive oxygen species contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia, a respiratory condition that affects preterm infants. To better understand the mechanisms of susceptibility to oxidant stress in neonatal lungs, we evaluated the role of genetic background in response to oxidant stress in the neonatal lung by exposing mice from 36 inbred strains to hyperoxia (95% O2) for 72 h after birth. Comparative mapping of chromosome 6 quantitative trait loci identified the M2 mAChR gene as a candidate susceptibility gene. Interestingly, one mouse strain carried a non-synonymous coding single-nucleotide polymorphism (SNP) in the M2 receptor gene that caused an amino acid substitution (P265L) that resulted in significantly reduced hyperoxia-induced inflammation, as compared to strains without this SNP. Moreover, hyperoxia-induced lung injury was significantly reduced in neonatal mice lacking M3 receptors. These findings shed new light on the pathways involved in oxidative lung injury in neonates. (Nichols JL, et al. Genome-wide association mapping of acute lung injury in neonatal inbred mice. FASEB J 28, 2538-50, 2014)
Showing the most recent 10 out of 62 publications
