Search tips
Search criteria

Results 1-5 (5)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  Gap Junction-Mediated Death of Retinal Neurons Is Connexin and Insult Specific: A Potential Target for Neuroprotection 
The Journal of Neuroscience  2014;34(32):10582-10591.
Secondary cell death via gap junctions (GJs) plays a role in the propagation of neuronal loss under a number of degenerative disorders. Here, we examined the role of GJs in neuronal death in the retina, which has arguably the most diverse expression of GJs in the CNS. Initially, we induced apoptotic death by injecting single retinal ganglion cells and glia with cytochrome C and found that this resulted in the loss of neighboring cells to which they were coupled via GJs. We next found that pharmacological blockade of GJs eradicated nearly all amacrine cell loss and reduced retinal ganglion cell loss by ∼70% after induction of either excitotoxic or ischemic insult conditions. These data indicate that the GJ-mediated secondary cell death was responsible for the death of most cells. Whereas genetic deletion of the GJ subunit Cx36 increased cell survivability by ∼50% under excitotoxic condition, cell loss in Cx45 knock-out mouse retinas was similar to that seen in wild-type mice. In contrast, ablation of Cx45 reduced neuronal loss by ∼50% under ischemic insult, but ablation of Cx36 offered no protection. Immunolabeling of the connexins showed differential changes in protein expression consistent with their differing roles in propagating death signals under the two insults. These data indicate that secondary cell death is mediated by different cohorts of GJs dependent on the connexins they express and the type of initial insult. Our results suggest that targeting specific connexins offers a novel therapeutic strategy to reduce progressive cell loss under different neurodegenerative conditions.
PMCID: PMC4200109  PMID: 25100592
bystander effect; cell death; connexin; gap junctions; neuroprotection; retina
2.  Somatostatin Modulates Voltage-Gated K+ and Ca2+ Currents in Rod and Cone Photoreceptors of the Salamander Retina 
We investigated the cellular localization in the salamander retina of one of the somatostatin [or somatotropin release-inhibiting factor (SRIF)] receptors, sst2A, and studied the modulatory action of SRIF on voltage-gated K+ and Ca2+ currents in rod and cone photoreceptors. SRIF immunostaining was observed in widely spaced amacrine cells, whose perikarya are at the border of the inner nuclear layer and inner plexiform layer. sst2A immunostaining was seen in the inner segments and terminals of rod and cone photoreceptors. Additional sst2A immunoreactivity was expressed by presumed bipolar and amacrine cells. SRIF, at concentrations of 100–500 nM, enhanced a delayed outwardly rectifying K+ current (IK) in both rod and cone photoreceptors. SRIF action was blocked in cells pretreated with pertussis toxin (PTX) and was substantially reduced by intracellular GDPβS. Voltage-gated L-type Ca2+ currents in rods and cones were differently modulated by SRIF. SRIF reduced Ca2+ current in rods by 33% but increased it in cones by 40%, on average. Both effects were mediated via G-protein activation and blocked by PTX. Ca2+-imaging experiments supported these results by showing that 500 nM SRIF reduced a K+-induced increase in intracellular Ca2+ in rod photoreceptor terminals but increased it in those of cones. Our results suggest that SRIF may play a role in the regulation of glutamate transmitter release from photoreceptors via modulation of voltage-gated K+ and Ca2+ currents.
PMCID: PMC3696031  PMID: 10648697
somatostatin; retina; Ca2+ channel; K+ channel; G-protein; patch clamp
3.  Trafficking of Presynaptic PMCA Signaling Complexes in Mouse Photoreceptors Requires Cav1.4 α1 Subunits 
PMCID: PMC3683349  PMID: 22183401
Calcium extrusion; Nob2; Photoreceptor; Cacna1f; Voltage-operated; PMCA; PMCA1; Ribbon synapse; Retina
5.  Calcium Homeostasis and Cone Signaling Are Regulated by Interactions between Calcium Stores and Plasma Membrane Ion Channels 
PLoS ONE  2009;4(8):e6723.
Calcium is a messenger ion that controls all aspects of cone photoreceptor function, including synaptic release. The dynamic range of the cone output extends beyond the activation threshold for voltage-operated calcium entry, suggesting another calcium influx mechanism operates in cones hyperpolarized by light. We have used optical imaging and whole-cell voltage clamp to measure the contribution of store-operated Ca2+ entry (SOCE) to Ca2+ homeostasis and its role in regulation of neurotransmission at cone synapses. Mn2+ quenching of Fura-2 revealed sustained divalent cation entry in hyperpolarized cones. Ca2+ influx into cone inner segments was potentiated by hyperpolarization, facilitated by depletion of intracellular Ca2+ stores, unaffected by pharmacological manipulation of voltage-operated or cyclic nucleotide-gated Ca2+ channels and suppressed by lanthanides, 2-APB, MRS 1845 and SKF 96365. However, cation influx through store-operated channels crossed the threshold for activation of voltage-operated Ca2+ entry in a subset of cones, indicating that the operating range of inner segment signals is set by interactions between store- and voltage-operated Ca2+ channels. Exposure to MRS 1845 resulted in ∼40% reduction of light-evoked postsynaptic currents in photopic horizontal cells without affecting the light responses or voltage-operated Ca2+ currents in simultaneously recorded cones. The spatial pattern of store-operated calcium entry in cones matched immunolocalization of the store-operated sensor STIM1. These findings show that store-operated channels regulate spatial and temporal properties of Ca2+ homeostasis in vertebrate cones and demonstrate their role in generation of sustained excitatory signals across the first retinal synapse.
PMCID: PMC2725299  PMID: 19696927

Results 1-5 (5)