Expression of Nicotinic Acetylcholine Receptor α4 and β2 Subunits on Direction-Selective Retinal Ganglion Cells in the Rabbit

Lee, Jung Hoon; Kim, Hyun Jin; Ahn, Chang-Hyun; Jeon, Chang‐Jin

doi:10.1267/ahc.16024

Cited by 6 publications

(2 citation statements)

References 57 publications

(109 reference statements)

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“…Tocris ( www.tocris.com ) lists epibatidine as a high-affinity nicotinic agonist (Ki values = 0.02 and 233 nM for α4β2 and α7 nicotinic receptors respectively). Together, these results and others indicate the presence of different types of nAChRs [α3, ( 65 ); α4, ( 63 , 66 )] in the mammalian retina, including the α7 nAChR ( 67 ).…”

Section: Resultssupporting

confidence: 70%

Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease

Linn¹

2023

Front. Ophthalmol.

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The role of acetylcholine (ACh) in visual processing in the mammalian retina has been the focus of research for many decades. Pioneering work on the localization of ACh discovered that the neurotransmitter is synthesized and stored in a distinct subpopulation of amacrine (starburst) cells. It has been shown that ACh release is regulated to a low resting “tonic” level, much like what is observed at the neuromuscular junction (NMJ). If there were a dysfunction in the tonic release of ACh, might post-synaptic changes render the targets of ACh [i.e., retinal ganglion cells (RGCs)] vulnerable to disease? During my time at Pharmacia & Upjohn (PNU), selective nicotinic ACh receptor (nAChR) agonists (e.g., PNU-282987) were developed as a possible therapy for central nervous system (CNS) diseases. As RGCs are the main targets of neurodegeneration in glaucoma, could the activation of this target provide neuroprotection? In response to this question, experiments to identify alpha7 nAChRs in the retina (i.e., target ID studies) followed by “proof-of-concept” experiments were conducted. Target ID studies included binding studies with retinal homogenates, [125I]-alpha-bungarotoxin (α-BTX) autoradiography, and fluorescently tagged α-BTX binding in retinal slices. Imaging studies of intracellular calcium dynamics in the retinal slice were conducted. Reverse transcription-polymerase chain reaction (RT-PCR) analysis with alpha7 nAChR knockout mice using the “laser-capture microdissection” technique, in situ hybridization studies, and RT-PCR analysis of the human retina were conducted. Collectively, these experiments confirmed the presence of alpha7 nAChRs on specific cells in the retina. “Proof-of-concept” neuroprotection studies demonstrated that PNU-282987 provided significant protection for RGCs. This protection was dose dependent and was blocked with selective antagonists. More recently, evidence for the generation of new RGCs has been reported with PNU-282987 in rodents. Interestingly, the appearance of new RGCs is more pronounced with eye-drop application than with intravitreal injection. One could postulate that this reflects the neurogenic activation of alpha7 receptors on the retinal pigment epithelium (RPE) (eye drops) vs. a neuroprotective effect on RGCs (injections). In conclusion, there does appear to be a cholinergic retinal “tone” associated with RGCs that could be utilized as a neuroprotective therapy. However, a distinct cholinergic neurogenic mechanism also appears to exist in the outer retina that could possibly be exploited to generate new RGCs lost through various disease processes.

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Section: Resultssupporting

confidence: 70%

Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease

Linn¹

2023

Front. Ophthalmol.

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“…the cell body. For example, in both retinal ganglion cells and serotoninergic neurons in the dorsal raphe nucleus, alpha4 nAChRs are localized on dendrites ( 45 , 46 ). In the cerebral cortex and hippocampus, M1 mAChRs are also rarely observed on cell bodies, being preferentially located on dendrites and spines of pyramidal cells ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Acetylcholine regulation of GnRH neuronal activity: A circuit in the medial septum

Shostak

Constantin²,

Flannery³

et al. 2023

Front. Endocrinol.

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In vertebrates, gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility by regulating gonadotrophs in the anterior pituitary. While it is known that acetylcholine (ACh) influences GnRH secretion, whether the effect is direct or indirect, and the specific ACh receptor (AChR) subtype(s) involved remain unclear. Here, we determined 1) whether ACh can modulate GnRH cellular activity and 2) a source of ACh afferents contacting GnRH neurons. Calcium imaging was used to assay GnRH neuronal activity. With GABAergic and glutamatergic transmission blocked, subtype-specific AChR agonists and antagonists were applied to identify direct regulation of GnRH neurons. ACh and nicotine caused a rise in calcium that declined gradually back to baseline after 5-6 min. This response was mimicked by an alpha3-specific agonist. In contrast, muscarine inhibited GnRH calcium oscillations, and blocking M2 and M4 together prevented this inhibition. Labeling for choline acetyltransferase (ChAT) and GnRH revealed ChAT fibers contacting GnRH neurons, primarily in the medial septum (MS), and in greater number in females than males. ChAT positive cells in the MS are known to express p75NGFRs. Labeling for p75NGFR, ChAT and GnRH indicated that ChAT fibers contacting GnRH cells originate from cholinergic cells within these same rostral areas. Together, these results indicate that cholinergic cells in septal areas can directly regulate GnRH neurons.

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NMDA Receptor Activation and Ca2+/PKC Signaling in Nicotine-Induced GABA Transport Shift in Embryonic Chick Retina

et al. 2023

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Expression of Nicotinic Acetylcholine Receptor α4 and β2 Subunits on Direction-Selective Retinal Ganglion Cells in the Rabbit

Cited by 6 publications

References 57 publications

Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease

Target identification and validation of the alpha7 nicotinic acetylcholine receptor as a potential therapeutic target in retinal disease

Acetylcholine regulation of GnRH neuronal activity: A circuit in the medial septum

NMDA Receptor Activation and Ca2+/PKC Signaling in Nicotine-Induced GABA Transport Shift in Embryonic Chick Retina

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