Valdé s, Viviana, Matías Mosqueira, Sergio Rey, Rodrigo Del Rio, and Rodrigo Iturriaga. Inhibitory effects of NO on carotid body: contribution of neural and endothelial nitric oxide synthase isoforms. Am J Physiol Lung Cell Mol Physiol 284: L57-L68, 2003. First published September 6, 2002 10.1152/ajplung.00494.2001.-We tested the hypothesis that nitric oxide (NO) produced within the carotid body is a tonic inhibitor of chemoreception and determined the contribution of neuronal and endothelial nitric oxide synthase (eNOS) isoforms to the inhibitory NO effect. Accordingly, we studied the effect of NO generated from S-nitroso-Nacetylpenicillamide (SNAP) and compared the effects of the nonselective inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the selective nNOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole (TRIM) on chemosensory dose-response curves induced by nicotine and NaCN and responses to hypoxia (PO2 Ϸ 30 Torr). CBs excised from pentobarbitoneanesthetized cats were perfused in vitro with Tyrode at 38°C and pH 7.40, and chemosensory discharges were recorded from the carotid sinus nerve. SNAP (100 M) reduced the responses to nicotine and NaCN. L-NAME (1 mM) enhanced the responses to nicotine and NaCN by increasing their duration, but TRIM (100 M) only enhanced the responses to high doses of NaCN. The amplitude of the response to hypoxia was enhanced by L-NAME but not by TRIM. Our results suggest that both isoforms contribute to the NO action, but eNOS being the main source for NO in the cat CB and exerting a tonic effect upon chemoreceptor activity. chemoreceptor; nitric oxide THE VENTILATORY EFFECTS of nitric oxide (NO) and the role played by nitric oxide synthase (NOS) isoforms are complex (14,18,30). In the nucleus tractus solitarii, NO plays a significant excitatory role in sustaining the ventilatory response to hypoxia (14,18,35). However, several lines of evidence indicate that NO produced within the carotid body (CB) is an inhibitory modulator of hypoxic chemoreception (2,8,20,25,34,38). The administration of the precursor L-arginine, NO donor molecules (8,22,38), and NO gas (20) to the cat CB perfused in vitro reduces the chemosensory response to hypoxia. On the other hand, the inhibition of NOS increases the frequency of carotid chemosensory discharges (f x ) in the cat CB in situ and in vitro (19,38). However, little is known about the effects of NO on chemosensory responses induced by other excitatory stimuli, such as nicotine and NaCN. In a previous paper, we found that the NO donor sodium nitroprusside (SNP) reversibly reduced chemosensory responses induced by single doses of NaCN and nicotine in the superfused cat CB (2). In anesthetized cats, the NOS inhibitor N -nitro-L-arginine methyl ester (L-NAME) increased basal f x and enhanced responses to NaCN and dopamine (19). These results suggest that, besides the well-known inhibitory effect of NO on hypoxic chemoreception, NO may also modulate the responses to other stimuli.In the cat CB, NOS immunoreactivity and diaphorase activitie...

In neuronal cells the intracellular trafficking machinery controls the availability of neurotransmitter receptors at the plasma membrane, which is a critical determinant of synaptic strength. Metabotropic γ amino-butyric acid (GABA) type B receptors (GABABRs) are neurotransmitter receptors that modulate synaptic transmission by mediating the slow and prolonged responses to GABA. GABABRs are obligatory heteromers constituted by two subunits, GABABR1 and GABABR2. GABABR1a and GABABR1b are the most abundant subunit variants. GABABR1b is located in the somatodendritic domain whereas GABABR1a is additionally targeted to the axon. Sushi domains located at the N-terminus of GABABR1a constitute the only difference between both variants and are necessary and sufficient for axonal targeting. The precise targeting machinery and the organelles involved in sorting and transport have not been described. Here we demonstrate that GABABRs require the Golgi apparatus for plasma membrane delivery but that axonal sorting and targeting of GABABR1a operate in a pre-Golgi compartment. In the axon GABABR1a subunits are enriched in the endoplasmic reticulum (ER), and their dynamic behavior and colocalization with other secretory organelles like the ER-to-Golgi intermediate compartment (ERGIC) suggest that they employ a local secretory route. The transport of axonal GABABR1a is microtubule-dependent and kinesin-1, a molecular motor of the kinesin family, determines axonal localization. Considering that progression of GABABRs through the secretory pathway is regulated by an ER retention motif our data contribute to understand the role of the axonal ER in non-canonical sorting and targeting of neurotransmitter receptors.

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