Regulation of Membrane Targeting of the G Protein-coupled Receptor Kinase 2 by Protein Kinase A and Its Anchoring Protein AKAP79

The beta 2 adrenergic receptor (beta 2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The protein kinase A-anchoring protein AKAP79 influences beta 2AR phosphorylation by complexing PKA with the receptor at the membrane. Here we show that AKAP79 also regulates the ability of GRK2 to phosphorylate agonist-occupied receptors. In human embryonic kidney 293 cells, overexpression of AKAP79 enhances agonist-induced phosphorylation of both the beta 2AR and a mutant of the receptor that cannot be phosphorylated by PKA (beta 2AR/PKA-). Mutants of AKAP79 that do not bind PKA or target to the beta 2AR markedly inhibit phosphorylation of beta 2AR/PKA-. We show that PKA directly phosphorylates GRK2 on serine 685. This modification increases Gbeta gamma subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. Abrogation of the phosphorylation of serine 685 on GRK2 by mutagenesis (S685A) or by expression of a dominant negative AKAP79 mutant reduces GRK2-mediated translocation to beta 2AR and phosphorylation of agonist-occupied beta 2AR, thus reducing subsequent receptor internalization. Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization

Under the influence of genetics: how transdisciplinarity leads us to rethink social pathways to illness

This article describes both sociological and genetic theories of illness causation and derives propositions expected under each and under a transdisciplinary theoretical frame. The authors draw propositions from three theories -- fundamental causes, social stress processes, and social safety net theories -- and tailor hypotheses to the case of alcohol dependence. Analyses of a later wave of the Collaborative Study on the Genetics of Alcoholism reveal a complex interplay of the GABRA2 gene with social structural factors to produce cases meeting DSM/ICD diagnoses. Only modest evidence suggests that genetic influence works through social conditions and experiences. Further, women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; family support attenuates genetic influence; and childhood deprivation exacerbates genetic predispositions. These findings highlight the essential intradisciplinary tension in the role of proximal and distal influences in social processes and point to the promise of focusing directly on dynamic, networked sequences that produce different pathways to health and illness

Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence

Numerous reports have documented a high occurrence of sleep difficulties in drug-dependent populations, prompting researchers to characterize sleep profiles and physiology in drug abusing populations. This mini-review examines studies indicating that drug-dependent populations exhibit alterations in sleep homeostatic and restoration processes in response to sleep deprivation. Sleep deprivation is a principal sleep research tool that results in marked physiological challenge, which provides a means to examine sleep homeostatic processes in response to extended wakefulness. A report from our laboratory demonstrated that following recovery sleep from sleep deprivation, brain high-energy phosphates particularly beta–nucleoside triphosphate (beta-NTP) are markedly increased as measured with phosphorus magnetic resonance spectroscopy (MRS). A more recent study examined the effects of sleep deprivation in opiate-dependent methadone-maintained (MM) subjects. The study demonstrated increases in brain beta-NTP following recovery sleep. Interestingly, these increases were of a markedly greater magnitude in MM subjects compared to control subjects. A similar study examined sleep deprivation in cocaine-dependent subjects demonstrating that cocaine-dependent subjects exhibit greater increases in brain beta-NTP following recovery sleep when compared to control subjects. The studies suggest that sleep deprivation in both MM subjects and cocaine-dependent subjects is characterized by greater changes in brain ATP levels than control subjects. Greater enhancements in brain ATP following recovery sleep may reflect a greater disruption to or impact of sleep deprivation in drug dependent subjects, whereby sleep restoration processes may be unable to properly regulate brain ATP and maintain brain high-energy equilibrium. These studies support the notion of a greater susceptibility to sleep loss in drug dependent populations. Additional sleep studies in drug abusing populations are needed, particularly those that examine potential differential effects of sleep deprivation

Ariel - Volume 8 Number 3

Executive Editor James W. Lockard, Jr. Business Manager Neeraj K. Kanwal University News Richard J . Perry World News Doug Hiller Opinions Elizabeth A. McGuire Features Patrick P. Sokas Sports Desk Shahab S. Minassian Managing Editor Edward H. Jasper Managing Associate Brenda Peterson Photography Editor Robert D. Lehman. Jr. Graphics Christine M. Kuhnl

Inflation without Inflaton(s)

We propose a model for early universe cosmology without the need for fundamental scalar fields. Cosmic acceleration and phenomenologically viable reheating of the universe results from a series of energy transitions, where during each transition vacuum energy is converted to thermal radiation. We show that this `cascading universe' can lead to successful generation of adiabatic density fluctuations and an observable gravity wave spectrum in some cases, where in the simplest case it reproduces a spectrum similar to slow-roll models of inflation. We also find the model provides a reasonable reheating temperature after inflation ends. This type of model may also be relevant for addressing the smallness of the vacuum energy today.Comment: 13 pages, 4 figures, published versio

A new method for imaging nuclear threats using cosmic ray muons

Muon tomography is a technique that uses cosmic ray muons to generate three dimensional images of volumes using information contained in the Coulomb scattering of the muons. Advantages of this technique are the ability of cosmic rays to penetrate significant overburden and the absence of any additional dose delivered to subjects under study above the natural cosmic ray flux. Disadvantages include the relatively long exposure times and poor position resolution and complex algorithms needed for reconstruction. Here we demonstrate a new method for obtaining improved position resolution and statistical precision for objects with spherical symmetry