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Human evolutionary ecology stands to benefit by integrating theory and methods developed in movement ecology, and in turn, to make contributions to the broader field of movement ecology by leveraging our species' distinct attributes. In this paper, we review data and evolutionary models suggesting that major changes in socio-spatial behaviour accompanied the evolution of language. To illustrate and explore these issues, we present a comparison of GPS measures of the socio-spatial behaviour of Hadza hunter-gatherers of northern Tanzania to those of olive baboons (Papio anubis), a comparatively small-brained primate that is also savanna-adapted. While standard spatial metrics show modest differences, measures of spatial diversity, landscape exploration and spatiotemporal displacement between individuals differ markedly. Groups of Hadza foragers rapidly accumulate a vast, diverse knowledge pool about places and things over the horizon, contrasting with the baboon's narrower and more homogeneous pool of ecological information. The larger and more complex socio-spatial world illustrated by the Hadza is one where heightened cognitive abilities for spatial and episodic memory, navigation, perspective taking and communication about things beyond the here and now all have clear value.This article is part of the theme issue 'The spatial-social interface: a theoretical and empirical integration'.

What are the origins of object permanence? Despite widespread interest in this question, methodological barriers have prevented detailed analysis of how experience shapes the development of object permanence in newborn organisms. Here, we introduce an automated controlled-rearing method for studying the emergence of object permanence in strictly controlled virtual environments. We used newborn chicks as an animal model and recorded their behavior continuously (24/7) from the onset of vision. Across four experiments, we found that object permanence can develop rapidly, within the first few days of life. This ability developed even when chicks were reared in impoverished visual environments containing no object occlusion events. Object permanence failed to develop, however, when chicks were reared in environments containing temporally non-smooth objects (objects moving on discontinuous spatiotemporal paths). These results suggest that experience with temporally smooth objects facilitates the development of object permanence, confirming a key prediction of temporal learning models in computational neuroscience.

How do newborns learn to recognize objects? According to temporal learning models in computational neuroscience, the brain constructs object representations by extracting smoothly changing features from the environment. To date, however, it is unknown whether newborns depend on smoothly changing features to build invariant object representations. Here, we used an automated controlled-rearing method to examine whether visual experience with smoothly changing features facilitates the development of view-invariant object recognition in a newborn animal model--the domestic chick ("Gallus gallus"). When newborn chicks were reared with a virtual object that moved smoothly over time, the chicks created view-invariant representations that were selective for object identity and tolerant to viewpoint changes. Conversely, when newborn chicks were reared with a temporally non-smooth object, the chicks developed less selectivity for identity features and less tolerance to viewpoint changes. These results provide evidence for a "smoothness constraint" on the development of invariant object recognition and indicate that newborns leverage the temporal smoothness of natural visual environments to build abstract mental models of objects.

How long does it take for a newborn to recognize an object? Adults can recognize objects rapidly, but measuring object recognition speed in newborns has not previously been possible. Here we introduce an automated controlled-rearing method for measuring the speed of newborn object recognition in controlled visual worlds. We raised newborn chicks ("Gallus gallus") in strictly controlled environments that contained no objects other than a single virtual object, and then measured the speed at which the chicks could recognize that object from familiar and novel viewpoints. The chicks were able to recognize the object rapidly, at presentation rates of 125 ms per image. Further, recognition speed was equally fast whether the object was presented from familiar viewpoints or novel viewpoints (30 degree and 60 degree azimuth rotations). Thus, newborn chicks can recognize objects across novel viewpoints within a fraction of a second. These results demonstrate that newborns are capable of both rapid and invariant object recognition at the onset of vision.

Among mammals, post-reproductive life spans are currently documented only in humans and a few species of toothed whales. Here we show that a post-reproductive life span exists among wild chimpanzees in the Ngogo community of Kibale National Park, Uganda. Post-reproductive representation was 0.195, indicating that a female who reached adulthood could expect to live about one-fifth of her adult life in a post-reproductive state, around half as long as human hunter-gatherers. Post-reproductive females exhibited hormonal signatures of menopause, including sharply increasing gonadotropins after age 50. We discuss whether post-reproductive life spans in wild chimpanzees occur only rarely, as a short-term response to favorable ecological conditions, or instead are an evolved species-typical trait as well as the implications of these alternatives for our understanding of the evolution of post-reproductive life spans.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction.

BackgroundA striking aspect of evolution is that it often converges on similar trajectories. Evolutionary convergence can occur in deep time or over short time scales, and is associated with the imposition of similar selective pressures. Repeated convergent events provide a framework to infer the genetic basis of adaptive traits. The current study examines the genetic basis of secondary web loss within web-building spiders (Araneoidea). Specifically, we use a lineage of spiders in the genus Tetragnatha (Tetragnathidae) that has diverged into two clades associated with the relatively recent (5 mya) colonization of, and subsequent adaptive radiation within, the Hawaiian Islands. One clade has adopted a cursorial lifestyle, and the other has retained the ancestral behavior of capturing prey with sticky orb webs. We explore how these behavioral phenotypes are reflected in the morphology of the spinning apparatus and internal silk glands, and the expression of silk genes. Several sister families to the Tetragnathidae have undergone similar web loss, so we also ask whether convergent patterns of selection can be detected in these lineages.ResultsThe cursorial clade has lost spigots associated with the sticky spiral of the orb web. This appears to have been accompanied by loss of silk glands themselves. We generated phylogenies of silk proteins (spidroins), which showed that the transcriptomes of cursorial Tetragnatha contain all major spidroins except for flagelliform. We also found an uncharacterized spidroin that has higher expression in cursorial species. We found evidence for convergent selection acting on this spidroin, as well as genes involved in protein metabolism, in the cursorial Tetragnatha and divergent cursorial lineages in the families Malkaridae and Mimetidae.ConclusionsOur results provide strong evidence that independent web loss events and the associated adoption of a cursorial lifestyle are based on similar genetic mechanisms. Many genes we identified as having evolved convergently are associated with protein synthesis, degradation, and processing, which are processes that play important roles in silk production. This study demonstrates, in the case of independent evolution of web loss, that similar selective pressures act on many of the same genes to produce the same phenotypes and behaviors.

Nuclear histone deacetylase 4 (HDAC4) represses MEF2-mediated transcription, implicated in the development of heart failure. CaMKII-dependent phosphorylation drives nucleus-to-cytoplasm HDAC4 shuttling, but protein kinase A (PKA) is also linked to HDAC4 translocation. However, the interplay of CaMKII and PKA in regulating adult cardiomyocyte HDAC4 translocation is unclear. Here we sought to determine the interplay of PKA- and CaMKII-dependent HDAC4 phosphorylation and translocation in adult mouse, rabbit and human ventricular myocytes. Confocal imaging and protein analyses revealed that inhibition of CaMKII-but not PKA, PKC or PKD-raised nucleo-to-cytoplasmic HDAC4 fluorescence ratio (FNuc/FCyto) by ~ 50%, indicating baseline CaMKII activity that limits HDAC4 nuclear localization. Further CaMKII activation (via increased extracellular [Ca2+], high pacing frequencies, angiotensin II or overexpression of CaM or CaMKIIδC) led to significant HDAC4 nuclear export. In contrast, PKA activation by isoproterenol or forskolin drove HDAC4 into the nucleus (raising FNuc/FCyto by > 60%). These PKA-mediated effects were abolished in cells pretreated with PKA inhibitors and in cells expressing mutant HDAC4 in S265/266A mutant. In physiological conditions where both kinases are active, PKA-dependent nuclear accumulation of HDAC4 was predominant in the very early response, while CaMKII-dependent HDAC4 export prevailed upon prolonged stimuli. This orchestrated co-regulation was shifted in failing cardiomyocytes, where CaMKII-dependent effects predominated over PKA-dependent response. Importantly, human cardiomyocytes showed similar CaMKII- and PKA-dependent HDAC4 shifts. Collectively, CaMKII limits nuclear localization of HDAC4, while PKA favors HDAC4 nuclear retention and S265/266 is essential for PKA-mediated regulation. These pathways thus compete in HDAC4 nuclear localization and transcriptional regulation in cardiac signaling.

Cytonemes are specialized filopodia that mediate paracrine signaling in Drosophila and other animals. Studies using fluorescence confocal microscopy (CM) established their general paths, cell targets, and essential roles in signaling. To investigate details unresolvable by CM, we used high-pressure freezing and EM to visualize cytoneme structures, paths, contents, and contacts. We observed cytonemes previously seen by CM in the Drosophila wing imaginal disc system, including disc, tracheal air sac primordium (ASP), and myoblast cytonemes, and identified cytonemes extending into invaginations of target cells, and cytonemes connecting ASP cells and connecting myoblasts. Diameters of cytoneme shafts vary between repeating wide (206 ± 51.8 nm) and thin (55.9 ± 16.2 nm) segments. Actin, ribosomes, and membranous compartments are present throughout; rough ER and mitochondria are in wider proximal sections. These results reveal novel structural features of filopodia and provide a basis for understanding cytoneme cell biology and function.

Understanding how gendered economic roles structure space use is critical to evolutionary models of foraging behaviour, social organization and cognition. Here, we examine hunter-gatherer spatial behaviour on a very large scale, using GPS devices worn by Hadza foragers to record 2,078 person-days of movement. Theory in movement ecology suggests that the density and mobility of targeted foods should predict spatial behaviour and that strong gender differences should arise in a hunter-gatherer context. As predicted, we find that men walked further per day, explored more land, followed more sinuous paths and were more likely to be alone. These data are consistent with the ecology of male- and female-targeted foods and suggest that male landscape use is more navigationally challenging in this hunter-gatherer context. Comparisons of Hadza space use with space use data available for non-human primates suggest that the sexual division of labour likely co-evolved with increased sex differences in spatial behaviour and landscape use.

RationaleCaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF.ObjectiveTo measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice.Methods and resultsWe used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions.ConclusionsWe conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

Spiders are important predators in terrestrial ecosystems, yet we know very little about the principal feeding structures of spiders, the chelicerae, which are functionally equivalent to "jaws" or "mandibles" and are an extremely important aspect of spider biology. In particular, members of Palpimanoidea have evolved highly unusual cheliceral morphologies and functions, including high-speed, ballistic movements in mecysmaucheniid spiders, the fastest arachnid movements known thus far, and the elongated, highly maneuverable chelicerae of archaeids that use an attack-at-a-distance strategy. Here, using micro-Computed-Tomography scanning techniques, we perform a comparative study to examine cheliceral muscle morphology in six different spider specimens representing five palpimanoid families. We provide a hypothesis for homology in palpimanoid cheliceral muscles and then compare and contrast these findings with previous studies on other non-palpimanoid spiders. We document and discuss two sets of cheliceral muscles in palpimanoids that have not been previously observed in other spiders or which may represent a position shift compared to other spiders. In the palpimanoids, Palpimanus sp., Huttonia sp., and Colopea sp. showed similar cheliceral muscle anatomy. In Eriauchenius ranavalona, which has highly maneuverable chelicerae, some of the muscles have a more horizontal orientation, and there is a greater degree of cheliceral muscle divergence. In Zearchaea sp. and Aotearoa magna, some muscles have also shifted to a more horizontal orientation, and in Zearchaea sp., a species with a ballistic, high-speed predatory strike, there is a loss of cheliceral muscles. This research is a first step toward understanding cheliceral form and function across spiders.

Calcium-calmodulin dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac electrophysiology, calcium (Ca) balance, contraction, transcription, arrhythmias and progression to heart failure. CaMKII is readily activated at mouths of dyadic cleft Ca channels, but because of its low Ca-calmodulin affinity and presumed immobility it is less clear how CaMKII gets activated near other known, extra-dyad targets. CaMKII is typically considered to be anchored in cardiomyocytes, but while untested, mobility of active CaMKII could provide a mechanism for broader target phosphorylation in cardiomyocytes. We therefore tested CaMKII mobility and how this is affected by kinase activation in adult rabbit cardiomyocytes. We measured translocation of both endogenous and fluorescence-tagged CaMKII using immunocytochemistry, fluorescence recovery after photobleach (FRAP) and photoactivation of fluorescence. In contrast to the prevailing view that CaMKII is anchored near its myocyte targets, we found CaMKII to be highly mobile in resting myocytes, which was slowed by Ca chelation and accelerated by pacing. At low [Ca], CaMKII was concentrated at Z-lines near the dyad but spread throughout the sarcomere upon pacing. Nuclear exchange of CaMKII was also enhanced upon pacing- and heart failure-induced chronic activation. This mobilization of active CaMKII and its intrinsic memory may allow CaMKII to be activated in high [Ca] regions and then move towards more distant myocyte target sites.

Consumption of diets high in fat and/or fructose content promotes tissue inflammation, oxidative stress, and insulin resistance, activating signals (e.g. NF-κB/JNK) that downregulate the insulin cascade. Current evidence supports the concept that select flavonoids can mitigate obesity and type 2 diabetes (T2D). This work investigated if supplementation with the anthocyanidins (AC) cyanidin and delphinidin could attenuate the adverse consequences of consuming a high fat diet (HFD) in mice. Consumption of an AC-rich blend mitigated HFD-induced obesity, dyslipidemia and insulin resistance (impaired responses to insulin and glucose). HFD-fed mice were characterized by increased liver lipid deposition and inflammation, which were also attenuated upon AC supplementation. HFD caused liver oxidative stress showing an increased expression of NADPH oxidases, generators of superoxide and H2O2, and high levels of oxidized lipid-protein adducts. This was associated with the activation of the redox sensitive signals IKK/NF-κB and JNK1/2, and increased expression of the NF-κB-regulated PTP1B phosphatase, all known inhibitors of the insulin pathway. In agreement with an improved insulin sensitivity, AC supplementation inhibited oxidative stress, NF-κB and JNK activation, and PTP1B overexpression. Thus, cyanidin and delphinidin consumption either through diet or by supplementation could be a positive strategy to control the adverse effects of Western style diets, including overweight, obesity, and T2D. Modulation of inflammation, oxidative stress, and NF-κB/JNK activation emerge as relevant targets of AC beneficial actions.

Small animals possess intriguing morphological and behavioral traits that allow them to capture prey, including innovative structural mechanisms that produce ballistic movements by amplifying power [1-6]. Power amplification occurs when an organism produces a relatively high power output by releasing slowly stored energy almost instantaneously, resulting in movements that surpass the maximal power output of muscles [7]. For example, trap-jaw, power-amplified mechanisms have been described for several ant genera [5, 8], which have evolved some of the fastest known movements in the animal kingdom [6]. However, power-amplified predatory strikes were not previously known in one of the largest animal classes, the arachnids. Mecysmaucheniidae spiders, which occur only in New Zealand and southern South America, are tiny, cryptic, ground-dwelling spiders that rely on hunting rather than web-building to capture prey [9]. Analysis of high-speed video revealed that power-amplified mechanisms occur in some mecysmaucheniid species, with the fastest species being two orders of magnitude faster than the slowest species. Molecular phylogenetic analysis revealed that power-amplified cheliceral strikes have evolved four times independently within the family. Furthermore, we identified morphological innovations that directly relate to cheliceral function: a highly modified carapace in which the cheliceral muscles are oriented horizontally; modification of a cheliceral sclerite to have muscle attachments; and, in the power-amplified species, a thicker clypeus and clypeal apodemes. These structural innovations may have set the stage for the parallel evolution of ballistic predatory strikes.

RationaleCardiac myocyte contraction is caused by Ca(2+) binding to troponin C, which triggers the cross-bridge power stroke and myofilament sliding in sarcomeres. Synchronized Ca(2+) release causes whole cell contraction and is readily observable with current microscopy techniques. However, it is unknown whether localized Ca(2+) release, such as Ca(2+) sparks and waves, can cause local sarcomere contraction. Contemporary imaging methods fall short of measuring microdomain Ca(2+)-contraction coupling in live cardiac myocytes.ObjectiveTo develop a method for imaging sarcomere level Ca(2+)-contraction coupling in healthy and disease model cardiac myocytes.Methods and resultsFreshly isolated cardiac myocytes were loaded with the Ca(2+)-indicator fluo-4. A confocal microscope equipped with a femtosecond-pulsed near-infrared laser was used to simultaneously excite second harmonic generation from A-bands of myofibrils and 2-photon fluorescence from fluo-4. Ca(2+) signals and sarcomere strain correlated in space and time with short delays. Furthermore, Ca(2+) sparks and waves caused contractions in subcellular microdomains, revealing a previously underappreciated role for these events in generating subcellular strain during diastole. Ca(2+) activity and sarcomere strain were also imaged in paced cardiac myocytes under mechanical load, revealing spontaneous Ca(2+) waves and correlated local contraction in pressure-overload-induced cardiomyopathy.ConclusionsMultimodal second harmonic generation 2-photon fluorescence microscopy enables the simultaneous observation of Ca(2+) release and mechanical strain at the subsarcomere level in living cardiac myocytes. The method benefits from the label-free nature of second harmonic generation, which allows A-bands to be imaged independently of T-tubule morphology and simultaneously with Ca(2+) indicators. Second harmonic generation 2-photon fluorescence imaging is widely applicable to the study of Ca(2+)-contraction coupling and mechanochemotransduction in both health and disease.

Although Madagascar is an ancient fragment of Gondwana, the majority of taxa studied thus far appear to have reached the island through dispersal from Cenozoic times. Ancient lineages may have experienced a different history compared to more recent Cenozoic arrivals, as such lineages would have encountered geoclimatic shifts over an extended time period. The motivation for this study was to unravel the signature of diversification in an ancient lineage by comparing an area known for major geoclimatic upheavals (Madagascar) versus other areas where the environment has been relatively stable. Archaeid spiders are an ancient paleoendemic group with unusual predatory behaviors and spectacular trophic morphology that likely have been on Madagascar since its isolation. We examined disparities between Madagascan archaeids and their non-Madagascan relatives regarding timing of divergence, rates of trait evolution, and distribution patterns. Results reveal an increased rate of adaptive trait diversification in Madagascan archaeids. Furthermore, geoclimatic events in Madagascar over long periods of time may have facilitated high species richness due to montane refugia and stability, rainforest refugia, and also ecogeographic shifts, allowing for the accumulation of adaptive traits. This research suggests that time alone, coupled with more ancient geoclimatic events allowed for the different patterns in Madagascar.

RationaleBoth β-adrenergic receptor (β-AR) and Gq-coupled receptor (GqR) agonist-driven signaling play key roles in the events, leading up to and during cardiac dysfunction. How these stimuli interact at the level of protein kinase D (PKD), a nodal point in cardiac hypertrophic signaling, remains unclear.ObjectiveTo assess the spatiotemporal dynamics of PKD activation in response to β-AR signaling alone and on coactivation with GqR-agonists. This will test our hypothesis that compartmentalized PKD signaling reconciles disparate findings of PKA facilitation and inhibition of PKD activation.Methods and resultsWe report on the spatial and temporal profiles of PKD activation using green fluorescent protein-tagged PKD (wildtype or mutant S427E) and targeted fluorescence resonance energy transfer-based biosensors (D-kinase activity reporters) in adult cardiomyocytes. We find that β-AR/PKA signaling drives local nuclear activation of PKD, without preceding sarcolemmal translocation. We also discover pronounced interference of β-AR/cAMP/PKA signaling on GqR-induced translocation and activation of PKD throughout the cardiomyocyte. We attribute these effects to direct, PKA-dependent phosphorylation of PKD-S427. We also show that phosphomimetic substitution of S427 likewise impedes GqR-induced PKD translocation and activation. In neonatal myocytes, S427E inhibits GqR-evoked cell growth and expression of hypertrophic markers. Finally, we show altered S427 phosphorylation in transverse aortic constriction-induced hypertrophy.Conclusionsβ-AR signaling triggers local nuclear signaling and inhibits GqR-mediated PKD activation by preventing its intracellular translocation. PKA-dependent phosphorylation of PKD-S427 fine-tunes the PKD responsiveness to GqR-agonists, serving as a key integration point for β-adrenergic and Gq-coupled stimuli.