Molecular Targets of Atropine- and Mamba Toxin 3-Mediated Inhibition of Form-Deprivation Myopia in the Chick: A Case of Mistaken Receptor Identity?
Myopia is a refractive disorder characterized by the inability to see distant objects clearly. It is the most common childhood vision disorder, and the leading cause of adult visual impairment world-wide. Myopia prevalence is rising rapidly; it is estimated that 2.5 billion people will be affected by 2030, and any degree of myopia increases the risk of blindness-inducing comorbidities. There are no universally accepted pharmaceutical therapies to slow myopia progression, but some success has been found with the muscarinic acetylcholine receptor (mAChR) antagonist atropine. There remains a paucity of investigations into the ocular signalling cascades modulated by atropine-treatment. Research in this area has been based on the assumption that because atropine, and a few other mAChR antagonists, inhibit myopia at extremely high concentrations, mAChRs must regulate myopia progression. Regulation of eye growth by mAChRs has never been proven conclusively. Here, I report that myopia-inhibition by atropine is dependent on induction of nitric oxide (NO), and that exogenous NO is sufficient to inhibit experimentally-induced form-deprivation myopia (FDM) on its own. In addition, I provide evidence that disproves the assumption that mAChRs are responsible for atropine- and mamba toxin 3-mediated myopia-inhibition in the chick. First, I demonstrate that alpha2-adrenoceptor (ADRA2) agonists can dose-dependently inhibit FDM. Second, I show that myopia-inhibiting mAChR antagonists can bind to, and block signalling by, human alpha2A-adrenoceptors (ADRA2A). Furthermore, I show that the relative inhibitory potencies (pIC50’s) of myopia-inhibiting mAChR antagonists at ADRA2A correlate better with their reported abilities to inhibit FDM in the chick than their relative pIC50’s at human and chicken mAChR M4. My data further our understanding of how the eye may know how large to grow. They provide two novel alternative targets for anti-myopia therapies (NO & ADRA2s), both of which would eliminate the most significant side-effects of atropine-treatment. They provide a range in which mAChR antagonists should be expected to act in a “specific” manner at human and chicken mAChR M4, and reinforce the need for caution in attributing the effects of high concentration drug to a specific receptor target.
Neuroscience, Ophthalmology, Pharmacology
Carr, B. J. (2017). Molecular Targets of Atropine- and Mamba Toxin 3-Mediated Inhibition of Form-Deprivation Myopia in the Chick: A Case of Mistaken Receptor Identity? (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/26995