Evidence for a functional adrenomedullin signaling pathway in the mouse retina.
OBJECTIVE
Adrenomedullin (ADM) is a small, secreted peptide often associated with vasodilation. However, ADM can also function as a neurotransmitter/neuromodulator, and studies suggest ADM is upregulated in the eye in several ocular diseases. However, no studies to date have described an ADM signaling pathway in the retina.


METHODS
PCR, immunocytochemistry, nitric oxide imaging, western blots, and a nitrite assay were used to determine the localization of the components of the ADM signaling pathway in the mouse retina.


RESULTS
We used reverse-transcriptase polymerase chain reaction to show that ADM and its primary receptor, calcitonin-receptor-like receptor, along with its associated receptor activity modifying proteins 2 and 3 are expressed in the retina. Using immunocytochemistry, we detected ADM staining throughout the retina in the photoreceptor outer segments, the outer nuclear layer, Müller and amacrine cell somata in the inner nuclear layer, and some somata in the ganglion cell layer. We found that calcitonin-receptor-like receptor and receptor activity modifying protein 2 had localization patterns similar to ADM, especially in somata in the inner nuclear and ganglion cell layers. Finally, we showed that the ADM receptor was functional in the retina. Stimulation of isolated retinas with ADM increased cyclic adenosine monophosphate- and cyclic guanosine monophosphate-like immunoreactivity, as well as nitric oxide production.


CONCLUSIONS
These results are the first to show that ADM and functional ADM receptors are present in the retina. Since ADM is increased in eyes with ocular pathologies such as diabetic retinopathy, glaucoma, retinitis pigmentosa, and uveitis, the ADM signaling pathway may provide a new target for ameliorating these retinal pathologies.
Boston University, Laboratory of Visual Neurobiology, Department of Biology, Boston, MA 02215, USA.
Jan
J
Blom
Thomas J
TJ
Giove
Winnie W
WW
Pong
Todd A
TA
Blute
William D
WD
Eldred
D053607:Adrenomedullin / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D009569:Nitric Oxide; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000378:metabolism*; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*
D058286:Calcitonin Receptor-Like Protein; D005136:Eye Proteins; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D053607:Adrenomedullin; D009569:Nitric Oxide; D000242:Cyclic AMP; D006152:Cyclic GMP