Adenosine as a signaling molecule in the retina: biochemical and developmental aspects

Abstract

The nucleoside adenosine plays an important role as a neurotransmitter or neuromodulator in the central nervous system, including the retina. In the present paper we review compelling evidence showing that adenosine is a signaling molecule in the developing retina. In the chick retina, adenosine transporters are present since early stages of development before the appearance of adenosine A1 receptors modulating dopamine-dependent adenylate cyclase activity orA2 receptors that directly activate the enzyme. Experiments using retinal cell cultures revealed that adenosine is taken up by specific cell populations that when stimulated by depolarization or neurotransmitters such as dopamine or glutamate, release the nucleoside through calciumdependent transporter-mediated mechanisms. The presence of adenosine in the extracellular medium and the long-term activation of adenosine receptors is able to regulate the survival of retinal neurons and blocks glutamate excitoxicity. Thus, adenosine besides working as a neurotransmitter or neuromodulator in the mature retina, is considered as an important signaling molecule during retinal development having important functions such as regulation of neuronal survival and differentiation.

A Circadian Clock and Light/Dark Adaptation Differentially Regulate Adenosine in the Mammalian Retina

“…Although it was not possible under our experimental conditions (retina isolated from the epithelium) to observe full recovery of the extracellular adenosine level in the dark after a period of intense light illumination, our observations nonetheless indicate that during bright light illumination, the extracellular level of adenosine is likely the lowest. Overall, our results are in complete agreement with the darkness-and nighttimemimicking effects of exogenous adenosine in the vertebrate retina that have been reported previously (Blazynski and Perez, 1991;Rey and Burnside, 1999;Paes-De-Carvalho, 2002;Sun et al, 2002;Stella et al, 2003).…”

“…In fact, dark adaptation during the day has been reported to decrease the oxygen tension of the mammalian retina and especially in the synaptic layers and outer nuclear layer, where it reaches 0 mmHg (Linsenmeier, 1986;Ahmed et al, 1993). If the clock produces a slight hypoxic-like state at night, then the resultant increase in adenosine may have a neuroprotective effect (Dunwiddie and Masino, 2001;Latini and Pedata, 2001;Paes-De-Carvalho, 2002) in addition to its neuromodulatory role.…”

“…In fact, a growing body of evidence indicates that adenosine is an important neuromodulator in the vertebrate retina (Blazynski and Perez, 1991;Paes-De-Carvalho, 2002), as indicated by the presence of retinal adenosine metabolic pathway enzymes and receptor subtypes A 1 and A 2A and by the effects of exogenous adenosine on the physiology of retinal neurons. However, the sources of extracellular adenosine in the retina are unknown and direct measurements of how light/dark adaptation affects endogenous adenosine are still lacking.…”

Local Modulation of Retinal Vein Tone

“…Adenosine is a signaling molecule in the retina. 35 Adenosine, along with the excitatory amino acids glutamate and aspartate, is known to be released from ischemic and hypoxic neural tissue. 36,37 We have demonstrated an asymmetrical response to exogenous adenosine in retinal arteries in that extraluminal administration of adenosine produces a dosedependent dilation, whereas intraluminal adenosine fails to produce a significant dilation response.…”

Therapeutic Opportunities for Caffeine and A_2A Receptor Antagonists in Retinal Diseases

“…Moreover, beyond the well-described role of A 2A R during CNS development, the genetic deletion of A 2A R promotes the development of relative myopia [90], demonstrating the importance of A 2A R for normal eye function. The adenosinergic system is present in the retina from early embryogenesis, and it also plays an important role for normal retinal development [91,92]. …”