Bovine PDE␦ was originally copurified with rod cGMP phosphodiesterase (PDE) and shown to interact with prenylated, carboxymethylated C-terminal Cys residues. Other studies showed that PDE␦ can interact with several small GTPases including Rab13, Ras, Rap, and Rho6, all of which are prenylated, as well as the Nterminal portion of retinitis pigmentosa GTPase regulator and Arl2/Arl3, which are not prenylated. We show by immunocytochemistry with a PDE␦-specific antibody that PDE␦ is present in rods and cones. We find by yeast two-hybrid screening with a PDE␦ bait that it can interact with farnesylated rhodopsin kinase (GRK1) and that prenylation is essential for this interaction. In vitro binding assays indicate that both recombinant farnesylated GRK1 and geranylgeranylated GRK7 co-precipitate with a glutathione S-transferase-PDE␦ fusion protein. Using fluorescence resonance energy transfer techniques exploiting the intrinsic tryptophan fluorescence of PDE␦ and dansylated prenyl cysteines as fluorescent ligands, we show that PDE␦ specifically binds geranylgeranyl and farnesyl moieties with a K d of 19.06 and 0.70 M, respectively. Our experiments establish that PDE␦ functions as a prenyl-binding protein interacting with multiple prenylated proteins.

The Lopu Range, located ~600 km west of Lhasa, exposes a continental high‐pressure metamorphic complex beneath India‐Asia (Yarlung) suture zone assemblages. Geologic mapping, 14 detrital U‐Pb zircon (n = 1895 ages), 11 igneous U‐Pb zircon, and nine zircon (U‐Th)/He samples reveal the structure, age, provenance, and time‐temperature histories of Lopu Range rocks. A hornblende‐plagioclase‐epidote paragneiss block in ophiolitic mélange, deposited during Middle Jurassic time, records Late Jurassic or Early Cretaceous subduction initiation followed by Early Cretaceous fore‐arc extension. A depositional contact between fore‐arc strata (maximum depositional age 97 ± 1 Ma) and ophiolitic mélange indicates that the ophiolites were in a suprasubduction zone position prior to Late Cretaceous time. Five Gangdese arc granitoids that intrude subduction‐accretion mélange yield U‐Pb ages between 49 and 37 Ma, recording Eocene southward trench migration after collision initiation. The south dipping Great Counter Thrust system cuts older suture zone structures, placing fore‐arc strata on the Kailas Formation, and sedimentary‐matrix mélange on fore‐arc strata during early Miocene time. The north‐south, range‐bounding Lopukangri and Rujiao faults comprise a horst that cuts the Great Counter Thrust system, recording the early Miocene (~16 Ma) transition from north‐south contraction to orogen‐parallel (E‐W) extension. Five early Miocene (17–15 Ma) U‐Pb ages from leucogranite dikes and plutons record crustal melting during extension onset. Seven zircon (U‐Th)/He ages from the horst block record 12–6 Ma tectonic exhumation. Jurassic—Eocene Yarlung suture zone tectonics, characterized by alternating episodes of contraction and extension, can be explained by cycles of slab rollback, breakoff, and shallow underthrusting—suggesting that subduction dynamics controlled deformation.

Falls in blood glucose induce hunger and initiate feeding. The lateral hypothalamic area (LHA) contains glucose-sensitive neurons (GSNs) and orexin neurons, both of which are stimulated by falling blood glucose and are implicated in hypoglycemia-induced feeding. We combined intracellular electrophysiological recording with fluorescein labeling of GSNs to determine their neuroanatomic and functional relationships with orexin neurons. Orexin A (1 mol/l) caused a 500% increase (P < 0.01) in spontaneous firing rate and rapid and lasting depolarization that was tetrodotoxin-resistant and thus a direct postsynaptic effect. Orexin A altered the intrinsic neuronal properties of GSNs, consistent with increased excitability. Confocal microscopy showed that GSNs were intimately related to orexin neurons: orexin-immunoreactive axons were frequently entwined around GSN dendrites, establishing close and putatively synaptic contacts. Orexin-cell axons also passed in close proximity to glucose-responsive neurons, which are inhibited by low glucose, but orexin A caused smaller depolarization than on GSNs and only a 200% increase in spontaneous firing rate (P < 0.05 vs. GSN). We conclude that GSNs are specific target neurons for orexin A and suggest that they may mediate, at least in part, the acute appetite-stimulating effect of orexin A. Orexin neurons may regulate GSNs so as to control the onset and termination of hypoglycemiainduced feeding. Diabetes 50:2431-2437, 2001 R educed availability of glucose, the brain's main metabolic fuel, causes intense hunger (1). The lateral hypothalamic area (LHA) is crucial to the hyperphagia induced by hypoglycemia and glucoprivation, as this feeding response is abolished by LHA lesions (1). The LHA neuronal systems that drive glucoprivic feeding are unknown, but promising candidates include the glucose-sensing neurons and orexin (hypocretin) neurons that are prominent in this region.Glucose-sensing neurons, which alter their firing behavior in response to changes in ambient glucose concentration, are found in the hypothalamus and in several other central nervous system regions (2). Glucose-sensitive neurons (GSNs) are inhibited by rising glucose concentrations but excited when glucose falls, whereas glucose-responsive neurons (GRNs) are stimulated as glucose rises and are inhibited by hypoglycemia (3,4). GSNs are particularly abundant in the LHA, where they account for 30 -40% of all neurons (3,5). These cells are stimulated directly by low glucose in vitro (3,6) but are also regulated indirectly in vivo, being inhibited by rising glucose levels in the hindbrain and viscera and by gastric distension (1,7). These indirect signals are presumed to be relayed to the LHA from the nucleus of the solitary tract (NTS) in the medulla, which contains glucose-sensing neurons and also receives vagal afferents from visceral glucose sensors and gastric stretch receptors (7). In view of these properties, lateral hypothalamic GSNs are assumed to participate in triggering and controlling glucoprivic feeding...

Inbreeding depression is a major evolutionary and ecological force influencing population dynamics and the evolution of inbreeding-avoidance traits such as mating systems and dispersal. Mating systems and dispersal are fundamental determinants of population genetic structure. Resolving the relationships among genetic structure, seasonal breeding-related mating systems and dispersal will facilitate our understanding of the evolution of inbreeding avoidance. The goals of this study were as follows: (i) to determine whether females actively avoided mating with relatives in a group-living rodent species, Brandt’s voles (Lasiopodomys brandtii), by combined analysis of their mating system, dispersal and genetic structure; and (ii) to analyze the relationships among the variation in fine-genetic structure, inbreeding avoidance, season-dependent mating strategies and individual dispersal. Using both individual- and population-level analyses, we found that the majority of Brandt’s vole groups consisted of close relatives. However, both group-specific FISs, an inbreeding coefficient that expresses the expected percentage rate of homozygosity arising from a given breeding system, and relatedness of mates showed no sign of inbreeding. Using group pedigrees and paternity analysis, we show that the mating system of Brandt’s voles consists of a type of polygyny for males and extra-group polyandry for females, which may decrease inbreeding by increasing the frequency of mating among distantly-related individuals. The consistent variation in within-group relatedness, among-group relatedness and fine-scale genetic structures was mostly due to dispersal, which primarily occurred during the breeding season. Biologically relevant variation in the fine-scale genetic structure suggests that dispersal during the mating season may be a strategy to avoid inbreeding and drive the polygynous and extra-group polyandrous mating system of this species.