Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4 −/− mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430-460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase-and phosphodiesterase 6-dependent but protein kinase G-independent. β-Adrenergic receptor kinase 1 (βARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, lightactivated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.hotorelaxation, the reversible relaxation of blood vessels to cold light, was initially described by Furchgott et al. in 1955 (1). Subsequent studies have attempted to define the signal transduction mechanisms responsible for this phenomenon. The process seems to be cGMP-dependent but endothelialindependent. The role of nitric oxide (NO) in photorelaxation has been controversial (2-7), with some studies showing that NOS inhibition with L-NAME not only fails to inhibit the response (2) but in some cases enhances and prolongs it (3). Moreover, several published reports examining photorelaxation demonstrate an attenuation of the response with each subsequent light stimulation. A number of investigators have proposed that NO dependence results from the photo-release of NO stores from nitrosothiols and that the endothelium and NOS are important for the repriming of these stores (stores that become depleted with each photo-stimulation); however, the source of those nitrosothiols has not as yet been clearly identified (6). Importantly, photo-release of NO occurs in the UV-A spectrum at 366 nm (4-6), a wavelength at which intravascular nitrosospecies and nitrite have the potential to release substantial quantities of NO (7). However, this wavelength is very different from that at which others have observed vascular responses. Given the controversy surrounding the photorelaxation mechanism, we postulated an entirely new mechanism: that photorelaxation i...
Chronic nicotine administration increases ␣42 neuronal nicotinic acetylcholine receptor (nAChR) density in brain. This upregulation probably contributes to the development and/or maintenance of nicotine dependence. nAChR up-regulation is believed to be triggered at the ligand binding site, so it is not surprising that other nicotinic ligands also up-regulate nAChRs in the brain. These other ligands include varenicline, which is currently used for smoking cessation therapy. Sazetidine-A (saz-A) is a newer nicotinic ligand that binds with high affinity and selectivity at ␣42* nAChRs. In behavioral studies, saz-A decreases nicotine self-administration and increases performance on tasks of attention. We report here that, unlike nicotine and varenicline, chronic administration of saz-A at behaviorally active and even higher doses does not up-regulate nAChRs in rodent brains. We used a newly developed method involving radioligand binding to measure the concentrations and nAChR occupancy of saz-A, nicotine, and varenicline in brains from chronically treated rats. Our results indicate that saz-A reached concentrations in the brain that were ϳ150 times its affinity for ␣42* nAChRs and occupied at least 75% of nAChRs. Thus, chronic administration of saz-A did not upregulate nAChRs despite it reaching brain concentrations that are known to bind and desensitize virtually all ␣42* nAChRs in brain. These findings reinforce a model of nicotine addiction based on desensitization of up-regulated nAChRs and introduce a potential new strategy for smoking cessation therapy in which drugs such as saz-A can promote smoking cessation without maintaining nAChR up-regulation, thereby potentially increasing the rate of long-term abstinence from nicotine.
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