Butterfly pitch-angle distribution of relativistic electrons in the outer radiation belt: Evidence of nonadiabatic scattering

In this paper we investigate the scattering of relativistic electrons in the nightside outer radiation belt (around the geostationary orbit). We consider the particular case of low geomagnetic activity (|Dst|\u3c20 nT), quiet conditions in the solar wind, and absence of whistler wave emissions. For such conditions we find several events of Van Allen probe observations of butterfly pitch angle distributions of relativistic electrons (energies about 1–3 MeV). Many previous publications have described such pitch angle distributions over a wide energy range as due to the combined effect of outward radial diffusion and magnetopause shadowing. In this paper we discuss another mechanism that produces butterfly distributions over a limited range of electron energies. We suggest that such distributions can be shaped due to relativistic electron scattering in the equatorial plane of magnetic field lines that are locally deformed by currents of hot ions injected into the inner magnetosphere. Analytical estimates, test particle simulations, and observations of the AE index support this scenario. We conclude that even in the rather quiet magnetosphere, small scale (magnetic local time (MLT)-localized) injection of hot ions from the magnetotail can likely influence the relativistic electron scattering. Thus, observations of butterfly pitch angle distributions can serve as an indicator of magnetic field deformations in the nightside inner magnetosphere. We briefly discuss possible theoretical approaches and problems for modeling such nonadiabatic electron scattering

A nonhuman primate model of inherited retinal disease.

Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general

Hsp40 Couples with the CSPα Chaperone Complex upon Induction of the Heat Shock Response

In response to a conditioning stress, the expression of a set of molecular chaperones called heat shock proteins is increased. In neurons, stress-induced and constitutively expressed molecular chaperones protect against damage induced by ischemia and neurodegenerative diseases, however the molecular basis of this protection is not known. Here we have investigated the crosstalk between stress-induced chaperones and cysteine string protein (CSPα). CSPα is a constitutively expressed synaptic vesicle protein bearing a J domain and a cysteine rich “string” region that has been implicated in the long term functional integrity of synaptic transmission and the defense against neurodegeneration. We have shown previously that the CSPα chaperone complex increases isoproterenol-mediated signaling by stimulating GDP/GTP exchange of Gαs. In this report we demonstrate that in response to heat shock or treatment with the Hsp90 inhibitor geldanamycin, the J protein Hsp40 becomes a major component of the CSPα complex. Association of Hsp40 with CSPα decreases CSPα-CSPα dimerization and enhances the CSPα-induced increase in steady state GTP hydrolysis of Gαs. This newly identified CSPα-Hsp40 association reveals a previously undescribed coupling of J proteins. In view of the crucial importance of stress-induced chaperones in the protection against cell death, our data attribute a role for Hsp40 crosstalk with CSPα in neuroprotection

Photoreceptor phosphodiesterase: Interaction of inhibitory γ subunit and cyclic GMP with specific binding sites on catalytic subunits.

Abstract The photoreceptor phosphodiesterase (PDE6) is the central effector enzyme in the phototransduction cascade of photoreceptor cells. It is the only known PDE isoform the activity of which is regulated by interaction with a heterotrimeric G protein. The rod PDE6 holoenzyme is a tetrameric protein consisting of two large catalytic α and β subunits and two small γ subunits, which serve as potent inhibitors of PDE6. In dark-adapted photoreceptors, the γ subunits maintain PDE6 activity at a low level. When exposed to light the visual pigment rhodopsin activates the retinal G protein, transducin, leading to release of the inhibitory action of the γ subunits. In addition to the active sites where cGMP is hydrolyzed, the α and β catalytic subunits have high-affinity, noncatalytic cGMP binding sites. These noncatalytic sites do not directly regulate cGMP catalysis at the active site, but rather can modulate the affinity with which the γ subunits bind to the catalytic subunits. This article describes a number of experimental approaches that have recently been developed for studying the interactions between catalytic and inhibitory subunits of PDE6, as well as the dynamics of cGMP binding to and dissociation from the PDE6 noncatalytic sites

Potency and Mechanism of Action of E4021, a Type 5 Phosphodiesterase Isozyme-Selective Inhibitor, on the Photoreceptor Phosphodiesterase Depend on the State of Activation of the Enzyme

The ability of inhibitors selective for the type 5 phosphodiesterase isozyme (PDE5) to act on the photoreceptor PDE isozyme (PDE6, the central effector enzyme for visual transduction) is poorly understood. Because PDE5 inhibitors are currently used as therapeutic agents, it is important to assess the potency and mechanism of action of this class of PDE inhibitor on PDE6. We show that E4021 (sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl]piperidine-4-carboxylate sesquihydrate) inhibits activated PDE6 (KI = 1.7 nM) as potently as PDE5. This makes E4021 the most potent inhibitor of PDE6 discovered to date. The effectiveness of E4021 to inhibit nonactivated PDE6 (with bound inhibitory γ subunits) is reduced 40-fold compared with the activated enzyme. Furthermore, at intermediate E4021 concentrations and high cGMP concentrations, nonactivated PDE undergoes activation of cGMP hydrolysis rather than inhibition. We demonstrate direct competition of E4021 and the γ subunits for binding to the catalytic site. Measurements of cGMP binding to noncatalytic regulatory sites on the catalytic subunits of PDE6 rule out an allosteric effect of E4021 by direct binding to these noncatalytic sites. We conclude that E4021 is a competitive inhibitor of cGMP hydrolysis and that the γ subunit also competes with both E4021 and substrate for catalytic site binding. An understanding of the effects of PDE5-targeted drugs on retinal PDE6 requires a knowledge of the complex interactions among substrate, drug, and inhibitory γ subunit at the catalytic site of both nonactivated and activated forms of PDE6