Connections of the superior paraolivary nucleus of the rat: II. Reciprocal connections with the tectal longitudinal column

The superior paraolivary nucleus (SPON), a prominent GABAergic center of the mammalian auditory brainstem, projects to the ipsilateral inferior colliculus (IC) and sends axons through the commissure of the IC (CoIC). Herein we demonstrate that the SPON is reciprocally connected with the recently discovered tectal longitudinal column (TLC). The TLC is a long and narrow structure that spans nearly the entire midbrain tectum longitudinally, immediately above the periaqueductal gray matter (PAG) and very close to the midline. Unilateral injections of biotinylated dextran into the SPON of the rat label abundant terminal fibers in the TLC of both sides, with an ipsilateral predominance. The SPON provides a dense innervation of the entire rostrocaudal extent of the ipsilateral TLC, and a relatively sparser innervation of the caudal and rostral portions of the contralateral TLC. SPON fibers reach the TLC by two routes: as collaterals of axons of the CoIC, and as axons that circumvent the ipsilateral IC before traveling in the deep layers of the superior colliculus (SC). The density of these projections identifies SPON as a significant source of input to the TLC. Other targets of the SPON discovered in this study include the deep layers of the SC and the PAG. The same experiments reveal numerous labeled cell bodies in the TLC, interspersed among the labeled SPON fibers. This observation suggests that the SPON is a significant target of TLC projections. The discovery of novel reciprocal connections between the SPON and the TLC opens unexpected avenues for investigation of sound processing in mammalian brainstem circuits

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

Background: Thyroid receptors, TRα and TRβ, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRβ isoform activation, TRα activation affects heart rates. Therefore, β-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600- to 1400-fold more potency and approximately two- to threefold more efficacy than atorvastatin (Lipitor©) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRα Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TRβ. The corresponding Arg282 of TRβ is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TRα, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TRβ, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T3. These results shed light into the β-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms-4

D and orange) bound to two hTR isoforms highlights the conformational variability associated with the Ser277 and Asn331 residues. This variability is mostly a result of the lack of the amine group in GC-1, but its presence in T.<p><b>Copyright information:</b></p><p>Taken from "Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms"</p><p>http://www.biomedcentral.com/1472-6807/8/8</p><p>BMC Structural Biology 2008;8():8-8.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2275733.</p><p></p

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms-3

β as computed from molecular dynamics simulations.<p><b>Copyright information:</b></p><p>Taken from "Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms"</p><p>http://www.biomedcentral.com/1472-6807/8/8</p><p>BMC Structural Biology 2008;8():8-8.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2275733.</p><p></p

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms-2

S as observed from molecular dynamics simulations. The greater flexibility of the Arg228 side chain relative to the Arg282 side chain can be observed by the larger RMS deviations. This flexiblity results from weaker anchoring of this side chain in hTRα. Two binding modes can be distinguished if one computes the CZ-C20 distance. The snapshots of Arg282 show practically the same productive conformation, locked in place by the strong interaction with the Asn331 side-chain. Asn331 (hTRβ) to Ser277 (hTRα) substitution removes these conformational restrains and allows Arg228 to sample a much wider range of conformations. The non-productive conformations encountered in the simulations resemble closely the non-productive conformations of Arg228 found in the crystallographic structures.<p><b>Copyright information:</b></p><p>Taken from "Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms"</p><p>http://www.biomedcentral.com/1472-6807/8/8</p><p>BMC Structural Biology 2008;8():8-8.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2275733.</p><p></p

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms-0

red, gray and blue correspond to regions I, II and III described in the text. Apolar residues are shown in gray, basic residues in blue (namely His435, Arg316, Arg282 and Arg320) and polar residues in orange (including Asn331).<p><b>Copyright information:</b></p><p>Taken from "Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms"</p><p>http://www.biomedcentral.com/1472-6807/8/8</p><p>BMC Structural Biology 2008;8():8-8.</p><p>Published online 31 Jan 2008</p><p>PMCID:PMC2275733.</p><p></p