Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa

Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers.

Toward A Political Ecology in Lydia Maria Child’s “Chocorua’s Curse”

“Chocorua's Curse,” Lydia Maria Child's retelling of a White Mountain legend, found its way into middle class Boston homes through its publication in the 1830 gift book, The Token, accompanied by an engraving based on a Thomas Cole painting. Child's short sketch contrasts with typical iterations of the tale—and with the several paintings of the dramatic pyramidal peak by Cole—by its inclusion of homes spaces, a female figure, and a sense of the landscape as a watershed and not merely the iconic mountain peak. In addition, using ideas about household economy, educational transmission, and sympathy, Child prefigures ways of writing about the ecological flow of energy and materials through systems that include human and nonhuman entities. With this reading, the poison intended for a “troublesome” fox is an essential part of the subsequent chain of revenge killings and doubles with the final curse on the waters. Using the trope of sympathetic transmission, I argue that Child anticipates ecological thinking through a gendered lens. Material and emotional energy move through human and nonhuman entities, and mindful consideration can perhaps thwart the disaster caused by the men who, as critics have noted, seem disengaged from larger social systems.

Neurons, Receptors, and Channels

Here, I recount some adventures that I and my colleagues have had over some 60 years since 1957 studying the effects of drugs and neurotransmitters on neuronal excitability and ion channel function, largely, but not exclusively, using sympathetic neurons as test objects. Studies include effects of centrally active drugs on sympathetic transmission; neuronal action and neuroglial uptake of GABA in the ganglia and brain; the action of muscarinic agonists on sympathetic neurons; the action of bradykinin on neuroblastoma-derived cells; and the identification of M-current as a target for muscarinic action, including experiments to determine its distribution, molecular composition, neurotransmitter sensitivity, and intracellular regulation by phospholipids and their hydrolysis products. Techniques used include electrophysiological recording (extracellular, intracellular microelectrode, whole-cell, and single-channel patch-clamp), autoradiography, messenger RNA and complementary DNA expression, antibody injection, antisense knockdown, and membrane-targeted lipidated peptides. I finish with some recollections about my scientific career, funding, and changes in laboratory life and pharmacology research over the past 60 years.

α2-Adrenergic receptor signalling in hypertension

Cardiovascular regulation by the sympathetic nervous system is mediated by activation of one or more of the nine known subtypes of the adrenergic receptor family; α1A-, α1B-, α1D-, α2A-, α2B-, α2C-, β1-, β2- and β3-ARs (adrenoceptors). The role of the α2-AR family has long been known to include presynaptic inhibition of neurotransmitter release, diminished sympathetic efferent traffic, vasodilation and vasoconstriction. This complex response is mediated by one of three subtypes which all uniquely affect blood pressure and blood flow. All three subtypes are present in the brain, kidney, heart and vasculature. However, each differentially influences blood pressure and sympathetic transmission. Activation of α2A-ARs in cardiovascular control centres of the brain lowers blood pressure and decreases plasma noradrenaline (norepinephrine), activation of peripheral α2B-ARs causes sodium retention and vasoconstriction, whereas activation of peripheral α2C-ARs causes cold-induced vasoconstriction. In addition, non-selective agonists elicit endothelium-dependent vasodilation and presynaptic inhibition of noradrenaline release. The evidence that each of these receptor subtypes uniquely participates in cardiovascular control is discussed in this review.