Getting ethics into practice.
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Decision Making↗
Biomedical subjects
Michael J Parker
Publications and source records attributed to Michael J Parker.
Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.
Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.
Amino Acid Sequence↗
PSD93 regulates synaptic stability at neuronal cholinergic synapses.
Neuronal cholinergic synapses play important roles in both the PNS and CNS. However, the mechanisms that regulate the formation, maturation, and stability of neuronal cholinergic synapses are poorly understood. In this study, we use the readily accessible mouse superior cervical ganglion (SCG) and submandibular ganglion (SMG) to examine the assembly of the postsynaptic complex of neuronal cholinergic synapses. We find that novel splicing forms of PSD93 (postsynaptic density 93) are expressed in SCG. By immunostaining, we show that PSD93 proteins precisely colocalize with neuronal nicotinic acetylcholine receptors (nAChRs) at synapses of the SCG and SMG. Subcellular fractionation demonstrates that PSD93 is enriched in the PSD fraction of SCG, and coimmunoprecipitation shows that PSD93 and neuronal nAChRs form a complex in vivo. Furthermore, two additional components of the well characterized glutamatergic postsynaptic complex, GKAP/SAPAP (guanylate kinase domain-associated protein/synapse-associated protein-associated protein) and Shank/ProSAP family proteins, are also present at neuronal cholinergic synapses. To assess the function of this protein complex at neuronal cholinergic synapses in vivo, we examined ganglia in mice that lack PSD93. We find that neuronal cholinergic synapses form properly in PSD93 null mice. After denervation, however, synaptic clusters of nAChRs disassemble much faster in mice lacking PSD93 than those in wild-type mice. These results demonstrate that PSD93 is a key component of the postsynaptic scaffold at neuronal cholinergic synapses and plays an important role in synaptic stability. In addition, these results suggest that the mechanism of postsynaptic scaffolding is conserved between neuronal cholinergic and glutamatergic synapses.
Alternative Splicing↗
Adding allergy to your practice.
The ability to blend the management of allergic disease into the general treatment of head and neck disease is core to the otolaryngologist's role as regional specialist of the upper aerodigestive tract. Allergy training is now considered an integral component of the residency curriculum established by the American Board of Otolaryngology. By obtaining any needed additional training through organizations such as the AAOA and by validating that education by obtaining fellowship status in the AAOA, the postgraduate otolaryngologist who adds allergy to his or her practice will find the techniques to be safe, effective, and of great benefits to patients.
Emergencies↗
Effects of pyridine ring substitutions on affinity, efficacy, and subtype selectivity of neuronal nicotinic receptor agonist epibatidine.
2'-Pyridine ring substituted analogs of epibatidine were assessed for equilibrium binding affinity, functional potency, and efficacy at rat neuronal nicotinic receptors expressed in Xenopus oocytes. Binding affinities were determined in membrane homogenates from oocytes expressing alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2, or alpha4beta4. Efficacy (relative to acetylcholine) and potency were measured electrophysiologically with oocytes expressing alpha3beta4, alpha4beta2, and alpha4beta4. Hydroxy, dimethylamino, and trifluoromethanesulfonate analogs had affinities too low for accurate measurement. The bromo analog had affinities 4- to 55-fold greater at beta2 than at beta4-containing receptors, modestly greater efficacy at alpha4beta4 than at alpha4beta2, and 5- to 10-fold greater potency at a4beta4 than at alpha3beta4 or alpha4beta2. The fluoro analog displayed affinities 52- to 875-fold greater at beta2- than at beta4-containing receptors, efficacy at alpha4beta4 receptors 3-fold greater than at alpha4beta2 and alpha3beta4, and was equipotent at all receptors tested. The norchloro analog showed affinities 114- to 3500-fold greater at beta2- than at beta4-containing receptors, 2-fold greater efficacy at alpha4beta2 and alpha4beta4 than at alpha3beta4, and 4- to 5-fold greater potency at alpha4beta4 and alpha3beta4 than at alpha4beta2. The amino analog displayed affinities 10- to 115-fold greater at beta2- than at beta4-containing receptors, 3-fold greater efficacy at alpha3beta4 than at alpha4beta2, and 2- to 4-fold greater potency at alpha3beta4 and alpha4beta4 than at alpha4beta2. Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at alpha4beta4 receptors) there were no significant correlations among these properties.
Animals↗