Neurovascular interaction and the pathophysiology of diabetic retinopathy

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Experimental Diabetes Research 2011 (2011): 693426, doi:10.1155/2011/693426.Diabetic retinopathy (DR) is the most severe of the several ocular complications of diabetes, and in the United States it is the leading cause of blindness among adults 20 to 74 years of age. Despite recent advances in our understanding of the pathogenesis of DR, there is a pressing need to develop novel therapeutic treatments that are both safe and efficacious. In the present paper, we identify a key mechanism involved in the development of the disease, namely, the interaction between neuronal and vascular activities. Numerous pathological conditions in the CNS have been linked to abnormalities in the relationship between these systems. We suggest that a similar situation arises in the diabetic retina, and we propose a logical strategy aimed at therapeutic intervention

Histidine suppresses zinc modulation of connexin hemichannels

Author Posting. © Marine Biological Laboratory, 2004. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 207 (2004): 188-190.Zinc has been shown to modulate hemichannel currents of connexins Cx35 and Cx38 in Xenopus oocytes. In both cases the effects were biphasic; i.e., low concentrations of zinc enhanced, whereas higher concentrations decreased, the magnitudes of the voltage-activated hemichannel currents. The present study was designed to determine the effects of zinc on hemichannels formed by Cx26, a connexin reportedly expressed on dendrites of carp horizontal cells and implicated in a mechanism for photoreceptor feedback. In addition, we examined whether histidine, a zinc chelator, would block the action of zinc on Cx26 hemichannel currents, or would exert a direct effect on those currents.This work was supported in part by Fight for Sight, PSC/CUNY Grant 66257-0035, and NCRR/NIH RCMI Award RR-03037 (RLC); NIH Grants EY-06516 (HR), EY-14557 (HR), EY-12028 (HQ); and a Senior Research Investigator Award from Research to Prevent Blindness (HR)

Potassium currents distinguish the two subtypes of morphologically distinct skate bipolar cells

Author Posting. © Marine Biological Laboratory, 2004. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 207 (2004): 191-194.Bipolar cells in the vertebrate retina are second-order neurons that convey visual information from photoreceptors to ganglion cells, the neurons that relay the message to the brain. Bipolar cells consist typically of multiple subtypes that differ in their morphology, synaptic connections, and response properties. The individual subtypes are thought to carry different aspects of the visual signal through the retina, and they often exhibit unique membrane properties and neurotransmitter receptors. In the all-rod skate retina, only two morphologically and pharmacologically distinct subtypes of bipolar cell have been identified thus far. The large-field bipolar cells, with extensive dendritic arbors, are glycine-insensitive, whereas the small-field bipolar cells, which have only one or two dendritic branches, are sensitive to glycine. In the present study, we explored further the membrane properties of these two subtypes of skate bipolar cell with emphasis on the voltage-sensitive potassium currents. Our results show that the cells exhibit different voltage-activated current profiles, suggesting that the signals they transmit contain different features of the visual scene.This study was supported in part by NIH Grant EY-12028 (HQ); Fight for Sight, PSC/CUNY Grant 66257-0035, and NCRR/NIH RCMI Award RR-03037 (RLC); NIH Grant EY-06516 and a Senior Research Investigator Award from Research to Prevent Blindness (HR)

Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue.

Photochemical switches represent a powerful method for improving pharmacological therapies and controlling cellular physiology. Here we report the photoregulation of GABA(A) receptors (GABA(A)Rs) by a derivative of propofol (2,6-diisopropylphenol), a GABA(A)R allosteric modulator, which we have modified to contain photoisomerizable azobenzene. Using α(1)β(2)γ(2) GABA(A)Rs expressed in Xenopus laevis oocytes and native GABA(A)Rs of isolated retinal ganglion cells, we show that the trans-azobenzene isomer of the new compound (trans-MPC088), generated by visible light (wavelengths ~440 nm), potentiates the γ-aminobutyric acid-elicited response and, at higher concentrations, directly activates the receptors. cis-MPC088, generated from trans-MPC088 by ultraviolet light (~365 nm), produces little, if any, receptor potentiation/activation. In cerebellar slices, MPC088 co-applied with γ-aminobutyric acid affords bidirectional photomodulation of Purkinje cell membrane current and spike-firing rate. The findings demonstrate photocontrol of GABA(A)Rs by an allosteric ligand, and open new avenues for fundamental and clinically oriented research on GABA(A)Rs, a major class of neurotransmitter receptors in the central nervous system

Characteristics of period doubling in the rat cone flicker ERG

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Experimental Eye Research 90 (2010): 196-202, doi:10.1016/j.exer.2009.10.006.When the eye is stimulated by a flickering light, the electroretinogram (ERG) and other electrophysiological responses in the visual pathway often exhibit period doubling. This phenomenon is manifested as an alternation in the shape of the response waveform from cycle to cycle, and also as spectral components at the half-fundamental frequency (F/2) and its odd multiples. Although period doubling has been described in humans as well as in other animals, its features in the rodent flicker ERG have not been characterized. We investigated the properties of period doubling in the rat cone flicker ERG elicited with full field, sinusoidal photic stimuli. Period doubling was observed when the temporal frequency of the stimulus was in the range of 20 to 30 Hz. The F/2 component of the Fourier spectrum of the ERG was more pronounced than its odd harmonics. The magnitude of the cycle-to-cycle variation in amplitude differed depending on whether measurements were based on peak-to-trough or trough-to-peak amplitudes, owing to the relative phase relationship between F/2 and F as a function of stimulus frequency. The frequency-response characteristics of period doubling varied with stimulus contrast, such that reducing the contrast shifted the peak F/2 amplitude to a lower stimulus frequency. Period doubling was evident in rat eyes in which PDA was administered intravitreally, indicating that the phenomenon can occur independently of OFF-pathway activity in the rat retina. The period doubling properties we observed in the flicker ERG response of the rat cone system provide constraints on the nature of the nonlinear feedback mechanism presumed to underlie the period doubling phenomenon.This work was supported by a grant from the Pearle Vision Foundation (HQ), the Joyce Schroeder Fund (HQ), NIH research grant EY08301 (KRA), NIH core grant EY01792, an Alcon Research Institute Award (HR), RPB Senior Scientific Investigator Awards (KRA, HR), and an unrestricted departmental award from Research to Prevent Blindness, Inc