Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes

A-kinase anchoring proteins (AKAPs) tether protein kinase A (PKA) and other signaling proteins to defined intracellular sites, thereby establishing compartmentalized cAMP signaling. AKAP-PKA interactions play key roles in various cellular processes, including the regulation of cardiac myocyte contractility. We discovered small molecules, 3,3'-diamino-4,4'-dihydroxydiphenylmethane (FMP-API-1) and its derivatives, which inhibit AKAP-PKA interactions in vitro and in cultured cardiac myocytes. The molecules bind to an allosteric site of regulatory subunits of PKA identifying a hitherto unrecognized region that controls AKAP-PKA interactions. FMP-API-1 also activates PKA. The net effect of FMP-API-1 is a selective interference with compartmentalized cAMP signaling. In cardiac myocytes, FMP-API-1 reveals a novel mechanism involved in terminating β-adrenoreceptor-induced cAMP synthesis. In addition, FMP-API-1 leads to an increase in contractility of cultured rat cardiac myocytes and intact hearts. Thus, FMP-API-1 represents not only a novel means to study compartmentalized cAMP/PKA signaling but, due to its effects on cardiac myocytes and intact hearts, provides the basis for a new concept in the treatment of chronic heart failure.     

Drought and Oxidative Load in the Leaves of C3 Plants: a Predominant Role for Photorespiration?

Although active oxygen species are produced at high rates inboth the chloroplasts and peroxisomes of the leaves of C₃ plants,most attention has focused on the potentially damaging consequencesof enhanced chloroplastic production in stress conditions suchas drought. This article attempts to provide quantitative estimatesof the relative contributions of the chloroplast electron transportchain and the glycolate oxidase reaction to the oxidative loadplaced on the photosynthetic leaf cell. Rates of photorespiratoryH₂O₂ production were obtained from photosynthetic and photorespiratoryflux rates, derived from steady-state leaf gas exchange measurementsat varying irradiance and ambient CO₂. Assuming a 10 % allocationof photosynthetic electron flow to the Mehler reaction, photorespiratoryH₂O₂ production would account for about 70 % of total H₂O₂ formedat all irradiances measured. When chloroplastic CO₂ concentrationrates are decreased, photorespiration becomes even more predominantin H₂O₂ generation. At the increased flux through photorespirationobserved at lower ambient CO₂, the Mehler reaction would haveto account for more than 35 % of the total photosynthetic electronflow in order to match the rate of peroxisomal H₂O₂ production.The potential signalling role of H₂O₂ produced in the peroxisomesis emphasized, and it is demonstrated that photorespiratoryH₂O₂ can perturb the redox states of leaf antioxidant pools.We discuss the interactions between oxidants, antioxidants andredox changes leading to modified gene expression, particularlyin relation to drought, and call attention to the potentialsignificance of photorespiratory H₂O₂ in signalling and acclimation.     

Low frequency of observed cowbird parasitism on eastern kingbirds: host rejection, effective nest defense, or parasite avoidance?

Eastern kingbird (Tyrannus tyrannus) nests rarely are parasitizedby brown-headed cowbirds (Molotrus ater). Kingbirds are oneof a dozen or so species known to eject cowbird eggs from theirnests. We hypothesized that either kingbirds eject cowbird eggsso quickly that researchers normally do not detect the eggsduring daily nest inspections, or that cowbirds avoid parasitizingkingbirds. We tested these alternative hypotheses by experimentallyintroducing real cowbird eggs into eastern kingbird nests duringthe pre-egg, early laying, late laying, and incubation stages.We recorded the interval between "parasitism" and ejection ofthe cowbird eggs. Although kingbirds ejected 87 of 88 cowbirdeggs placed in their nests, about 40% of the eggs remained innests for more than 24 h. Thus, during daily nest inspectionswe should have observed cowbird eggs if nests were parasitizedat all. In fact, we detected only one parasitized nest amongthe 402 inspected daily. The time for ejection was longest atnests parasitized early in laying, and shorter at nests parasitizedbefore and after. This variation in ejection times may reflectthe time kingbirds require to learn to recognize their own eggs.Although kingbirds defend their nests aggressively, they donot respond to female cowbirds as unique threats and do notguard their nests before sunrise when cowbirds lay. We concludethat cowbirds avoid parasitizing eastern kingbirds because theireggs most likely will be wasted. The rejection behavior persistspossibly because it is almost cost-free (a maximum of 0.07 kingbirdegg lost or damaged per cowbird egg ejected), or it evolvedin response to conspecific rather than cowbird parasitism. Foreignkingbird eggs introduced into nests at different nest stageswere ejected only during the pre-egg stage. This result supportsthe hypothesis that rejection behavior in eastern kingbirdsevolved in response to cowbird parasitism.     

Predation, sensitivity, and sex: why female black rhinoceroses outlive males

Among sexually dimorphic, polygynous mammals, adult femalestend to outlive males and respond more strongly to predatorsthan males. We asked whether a monomorphic, polygynous speciesvirtually immune to predation due to large size (black rhinoceros,Diceros bicornis) conforms to this pattern. Data on 193 interactionswith lions (Panthera leo) and spotted hyenas (Crocuta crocuta)in two nonhabituated populations in Namibia studied from 1991to 1993 revealed that: (1) females were more vigilant or aggressivethan males to either of the potential predators; and (2) whethersolitary or with calves, females attacked more often than males.Although solitary females tended to be more aggressive to lionsthan to hyenas, neither females with calves or males seemedto discriminate between the two carnivores. We also simulatedthe behavior of human predators (poachers) during 69 encounterswith rhinoceroses. While both sexes abandoned local sites becauseof our presence, females ran farther than males, covering upto 40 km in a day. These findings implicate a behavioral mechanismto explain why secondary sex ratios favor females - males aremore prone to human predation, a prediction consistent withdata from 12 populations throughout Africa. Black rhinocerosesappear to be an unanticipated exception to the well-establishedpattern of male-biased mortality in polygynous mammals; in theabsence of intense human predation (a recent event), male mortalityfails to exceed that of females, suggesting that intrasexualcompetition in a polygynous mammal: may not be the primary causeof unbalanced secondary sex ratios. Our results on the causesof sex differences in mortality and in responsiveness to differentpredators reinforce the relevance of behavioral ecology to conservation;such information is necessary for planning how best to minimizenegative human influences on the few remaining wild Africanrhinos.     

Differential expenditure of maternal resources in Antarctic fur seals, Arctocephalus gazella, at Heard Island, southern Indian Ocean

Maternal expenditure in lactating Antarctic fur seals (Arctocephalusgazella) was studied at Heard Island in the 1987 to 1988 summer/autumn.The mean birth mass, growth rate, and mass at 60 days of sonswere significantly greater than those of daughters. Maternalforaging trips lasted on average 5.9 days, and attendance boutslasted 1.5 days. Over the course of this study, foraging tripduration increased from 5.0 to 7.0 days, and attendance durationdeclined from 2.0 to 1.5 days. Pups lost 3.2% of their bodymass/day while their mothers foraged at sea, but gained massrapidly during periods of maternal attendance. Sons gained significantlymore body mass (1.9 kg) compared with daughters (1.3 kg) duringmaternal attendance, suggesting that sons consume more milk.Sex differences in mass gain were unrelated to pup age or bodymass. During 2-day maternal attendance bouts, sons gained mostof their mass (71%) during the first day, and daughters increasedmass at almost the same rate each day. The increase in massby sons during maternal attendance was significantly positivelyrelated to both the duration of their mothers' preceding andsubsequent foraging trips. In contrast, mass gained by daughterswas positively related to the duration of their mothers' attendance.Mass at 60 days age was negatively related to birth date insons, and positively related to birth mass in daughters. Thesedata indicate that (1) greater maternal resources are expendedon sons than on daughters, (2) sons receive greater maternalresources because they are male, and not because of their greaterbirth mass and body size, (3) different factors appear to beimportant in determining high postnatal growth in sons and daughters,and (4) demand for resources by sons can influence maternalbehavior and ultimately the level of resources received.     

Brood defense and brood size in the great tit (Parus major): a test of a model of unshared parental investment

To understand the interaction of the many contextual variablesthat affect parental behavior a number of static optimalitymodels have been developed. Among these the one by Lazarus andInglis (1986) is the only one to specifically predict the magnitudeof unshared parental investment (PI), i.e., of parental carethat carries a cost to the parent and that benefits all currentoffspring equally because it cannot be divided among them. Weinvestigated specifically how parent great tits (Parus major)gear their brood defense, a form of unshared PI, to the sizeof the brood at stake and to the risk incurred as a functionof the type of predator. The predators used were dummies ofthe great spotted woodpecker (Picoides major) and of the tawnyowl (Strix aluco). Normally, adults can approach the woodpeckerwith impunity; it had inflicted heavy losses to nestlings ofthe study populations of great tits near Wolfsburg, Lower Saxony.Parent great tits whose brood had been artificially reducedto two young responded to the dummy with less defense than dida control group with their pre-test brood size left intact.The nature of defense was qualitatively the same as that elicitedby a live woodpecker. Parents confronting the owl near theirbrood decreased their response with an artificial reductionin brood size much less. Because the owl used poses a seriousrisk to the defenders, as compared to the woodpecker, the resultlends powerful support to the "total loss" version of the modelof unshared PI; it predicts brood size to affect unshared PImore strongly when there is less risk to the parent. This interpretationis correct to the extent that one premise of the model, namelythat of uncompromised parentage, can be relaxed; great tit broodscontain a sizeable number of extrapair young. Males defendedtheir brood more strongly than did females. Sex and brood manipulationadded up linearly when affecting defense level, i.e., therewas no interaction.     

Trade-offs between postcopulatory riding and mate location in the blue milkweed beetle

In the blue milkweed beetle, Chrysochus cobaltinus (Coleoptera:Chrysomelidae), males remain stationary on females' backs forprolonged periods after a single, brief copulation. Lone malesoften attack pairs, and takeovers, in which rival males replacethe resident on the female's back, are common. I used removalexperiments to measure the effect of postcopulatory riding onlatency to remating. Females whose males were removed were morelikely to remate in the next 2 h than females that were allowedto remain paired. When females were removed, males were alsomore likely to remate in the 2-h period following removal thanwere males allowed to continue riding. This indicates that malesdelay remating by their mates at the expense of mating opportunitieswith additional females. The predicted reproductive successof guarding and nonguarding males was calculated using a modelbased upon experimentally derived latencies to remating andsimulated levels of last male paternity. Guarders outperformednonguarders when the proportion of offspring sired by the lastmale (P₂) was 0.4 or greater. Data on survival and lifetimemating success were used to evaluate survival trade-offs ofpostcopulatory riding. Although males sacrificed feeding timeto ride on females' backs, there was a positive relationshipbetween the proportion of time males spent riding and theirlongevity in the patch. These results indicate that postcopulatoryriding has no survival costs and indicate that postcopulatoryriding can be an effective paternity assurance mechanism evenwhen takeovers are common.     

Tail-flagging and other antipredator signals in white-tailed deer: new data and synthesis

We present a series of predictions concerning the costs andbenefits of antipredator behavior in ungulates and then testthem with data on white-tailed deer reacting to a human on foot.Costs of tail-flagging were apparently low and no data supportedthe idea that flagging serves as a warning signal to conspecifics,in either this or in other studies. Flagging deer fled at greaterspeeds than nonflaggers, indicating that flagging could possiblysignal prey's ability to escape. Dropping the tail at the endof the flight may additionally have made deer inconspicuous.Snorting did not appear directed at conspecifics, and comparativedata suggest that it signals that the predator has been detected.In contrast, foot-stamping was effective in alerting other deerto the observer's presence. Deer may have bounded to clear obstaclesalong their flight path. These preliminary data indicate thatseveral aspects of antipredator behavior in white-tailed deermay be pursuit-deterrent signals, and they therefore highlightthe necessity of observing natural predators' reactions to signalsgiven by deer in future studies.