Social neuroscience offers a window onto the mental origins of empathy. People must appreciate another mind, in order to empathize. People first categorize the other as human, assuming a mind, and then differentiate among social categories according to universal dimensions of perceived traits: warmth and competence. The least warm and competent groups (poor people, homeless, drug addicts) may even be denied humanity and a meaningful mind, according to both neural and behavioral responses to allegedly disgusting outcasts. Other groups may be instead envied and viewed as tools or automatons, that is, objectified. The patterns can reverse when perceivers must consider the other’s preferences, that is, appreciate the other’s mind.
social cognition; social neuroscience; empathy; dehumanization; objectification; mPFC; amygdala; prejudice; mind
The critical epidemiological data for estimating the prevalence of chemosensory disorders in the US are lacking. Several reasons for this will be discussed, including the time-consuming nature of many existing tests, stimulus delivery in a large-scale study, and the rationale for inclusion in a large-scale epidemiological study. The opportunity to include measures of chemosensory function in ongoing population-based studies has greatly facilitated the collection of recent data that establishes the high prevalence of olfactory impairment in older adults in the US population and the inability of self-report measures to capture this impairment. Epidemiological studies of the complete range of the population that involve chemosensory testing pose considerable challenges, but are critical to establishing prevalence rates. These studies have the potential to suggest prevention or intervention strategies for chemosensory impairment. Key issues, including cross-cultural issues in stimulus design, testing of special populations, cohort effects and optimal analyses of population-based chemosensory data, are considered.
olfaction; olfactory impairment; smell; odor; prevalence; epidemiology; population studies
The integrity of the tight junction barrier in epithelial and endothelial cells is critical to human health, but we still lack a detailed mechanistic knowledge of how the barrier is formed during development or responds to pathological and pharmacological insults. This limits our understanding of barrier dysfunction in disease and slows the development of therapeutic strategies. Recent studies confirm the long-maintained but previously unsupported view that the zonula occludens (ZO) proteins ZO-1 and ZO-2 are critical determinants of barrier formation. However, ZO proteins can also be components of adherens junctions, and recent studies suggest that ZO proteins may also promote the assembly and function of these junctions during epithelial morphogenesis. We review these studies and outline several recent observations that suggest that one role of ZO proteins is to regulate cytoskeletal dynamics at cell junctions. Finally, we propose a model by which the functional activities of ZO proteins in the adherens junction and tight junction are differentiated by a novel regulatory motif known as the U6 or acidic motif.
tight junction; adherens junction; zonula occludens; ZO-1; ZO-2; E-cadherin; cytoskeleton; MAGUK; PDZ; scaffold; permeability; epithelia; morphogenesis
As the second synapse in the central gustatory pathway of the rodent, the parabrachial nucleus of the pons (PbN) receives information about taste stimuli directly from the nucleus of the solitary tract (NTS). Data show that NTS cells amplify taste responses before transmitting taste-related signals to the PbN. NTS cells of varied response profiles send converging input to PbN cells, though input from NTS cells with similar profiles is more effective at driving PbN responses. PbN cells follow NTS input for the first 3 s of taste stimulation for NaCl, HCl, and quinine, but are driven in cyclic bursts throughout the response interval for sucrose. Analyses of the temporal characteristics of NTS and PbN responses show that both structures use temporal coding with equal effectiveness to identify taste quality. Thus, the NTS input to the PbN is comprehensive, in that PbN cells receive NTS input that could support broad sensitivity, systematic, in that the time course of PbN firing patterns depend reliably on the tastant, and efficient, in that information from the NTS is preserved as it is communicated across structures. Comparisons of NTS and PbN taste responses in rats form the basis for our speculation that in primates, where the central gustatory pathway does not synapse in the PbN, the function of the PbN in taste processing may have been incorporated into that of the NTS.
taste; parabrachial pons; temporal coding
Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical and behavioral approaches, we found that the peptide hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are expressed in mammalian taste buds. Furthermore, we found that GLP-1 signaling plays an important role in the modulation of taste sensitivity: GLP-1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami-tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.
glucagon-like peptide-1; hormone; sweet; umami; glutamate
Neuroscientists are now coming to appreciate that a significant degree of information processing occurs in the peripheral sensory organs of taste prior to signals propagating to the brain. Gustatory stimulation causes taste bud cells to secrete neurotransmitters that act on adjacent taste bud cells (paracrine transmitters) as well as on primary sensory afferent fibers (neurocrine transmitters). Paracrine transmission, representing cell-cell communication within the taste bud, has the potential to shape the final signal output that taste buds transmit to the brain. The following paragraphs summarize current thinking about how taste signals generally, and umami taste in particular, are processed in taste buds.
taste; neurotransmitters; serotonin; ATP; norepinephrine; synaptic transmission
Splenectomized mice express progressively increased numbers of platelets in the blood and reduced numbers of megakaryocytes in the marrow with age. The megakaryocytes in the marrow of these animals express reduced levels of Gata1, a transcription factor necessary for their maturation. In addition, the marrow from these animals expresses greater levels of cytokines (TGF-β, PDGF-α, and VEGF) known to be produced at high levels by megakaryocytes expressing reduced levels of Gata1. This high level of cytokine expression is in turn associated with active osteoblast proliferation localized to areas of the femur, where megakaryocytes expressing reduced Gata1 levels are also found. These results confirm the role of megakaryocytes as regulator of bone formation in mice and suggest that a cross-talk between the spleen and marrow may regulate the total numbers of hemopoietic niches present in an animal.
spleen; megakaryocytes; Gata1; bone formation
Research and outcomes with cochlear implants (CIs) have revealed a dichotomy in the cues necessary for speech and music recognition. CI devices typically transmit 16–22 spectral channels, each modulated slowly in time. This coarse representation provides enough information to support speech understanding in quiet and rhythmic perception in music, but not enough to support speech understanding in noise or melody recognition. Melody recognition requires some capacity for complex pitch perception, which in turn depends strongly on access to spectral fine structure cues. Thus, temporal envelope cues are adequate for speech perception under optimal listening conditions, while spectral fine structure cues are needed for music perception. In this paper, we present recent experiments that directly measure CI users’ melodic pitch perception using a melodic contour identification (MCI) task. While normal-hearing (NH) listeners’ performance was consistently high across experiments, MCI performance was highly variable across CI users. CI users’ MCI performance was significantly affected by instrument timbre, as well as by the presence of a competing instrument. In general, CI users had great difficulty extracting melodic pitch from complex stimuli. However, musically-experienced CI users often performed as well as NH listeners, and MCI training in less experienced subjects greatly improved performance. With fixed constraints on spectral resolution, such as it occurs with hearing loss or an auditory prosthesis, training and experience can provide a considerable improvements in music perception and appreciation.
cochlear implant; music perception; melodic contour identification
Recently the function of the sirtuin family, named after their homology to the Saccharomyces cerevisiae gene silent information regulator 2 (Sir2), has received a lot of attention, as their beneficial impact on longevity was linked to their effects on metabolic control. All sirtuins require nicotinamide adenine dinucleotide (NAD+) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels. SIRT1, the founding member of the sirtuin family, modulates many aspects of glucose and lipid homeostasis in almost all key metabolic tissues. Other members including SIRT2, SIRT3, and SIRT4 are also implicated in various metabolic processes. Here, we review the recent data related to the role of sirtuins in the control of metabolic homeostasis and possible underlying molecular mechanisms.
sirtuin; NAD+; deacetylase; ADP-ribosyl transferase; metabolic homeostasis; metabolic disorders
Cumulative evidence in rats suggests that the pontine parabrachial nucleus (PBN) is necessary for assigning hedonic value to taste stimuli. In a series of studies, our laboratory has investigated the parabrachial coding of sapid sucrose in normal and obese rats. First, using chronic microdialysis, we demonstrated that sucrose intake increases dopamine release in the nucleus accumbens, an effect that is dependent on oral stimulation and on concentration. The dopamine response was independent of the thalamocortical gustatory system, but was blunted substantially by lesions of the PBN. Similar lesions of the PBN but not the thalamic taste relay diminished cFos activation by sucrose ingestion in the nucleus accumbens. Recent single neuron recording studies demonstrated that processing of sucrose-evoked activity in the PBN is altered in the Otsuka Long Evans Tokushima Fatty (OLETF) rats that develop obesity due to chronic overeating and express increased avidity to sweet. Compared with lean controls, taste neurons in OLETF rats had reduced overall sensitivity to sucrose and altered concentration responses: decreased responses to lower and augmented responses to higher concentrations. The decreased sensitivity to sucrose was specific to NaCl-best neurons that also responded to sucrose, but the concentration effects were carried by the sucrose-specific neurons. Collectively, these findings support the hypothesis that the PBN enables taste stimuli to engage the reward system and, in doing so, influences food intake and body weight regulation. Obesity, in turn, may further alter the gustatory code via forebrain connections to the taste relays or hormonal changes consequent to weight gain.
taste; gustatory plasticity; pons; dopamine; appetite; obesity; diabetes
Though iron and oxygen are required to sustain essential biological processes, an excess of either can result in oxidative stress. Therefore, mammals tightly regulate cellular and systemic iron and oxygen homeostasis. At the cellular level, the hypoxia-inducible transcription factors (HIFs) are key mediators of oxygen homeostasis through their regulation of genes involved in anaerobic metabolism and oxygen delivery, among others. Iron regulatory proteins (IRPs) largely govern cellular iron homeostasis through their effects on the translation and stability of mRNAs involved in iron uptake, utilization, export, and storage. Here, we describe regulatory factors for each pathway that sense both iron and oxygen availability and coordinate the maintenance of mammalian iron and oxygen homeostasis at both the cellular and systemic levels.
iron; oxygen; hypoxia; iron regulatory protein (IRP); hypoxia-inducible factor (HIF); FBXL5; iron- and 2-oxoglutarate-dependent dioxygenase; hemerythrin
In birds as in other vertebrates, estrogens produced in the brain by aromatization of testosterone have widespread effects on behavior. Research conducted with male Japanese quail demonstrates that effects of brain estrogens on all aspects of sexual behavior, including appetitive and consummatory components as well as learned aspects, can be divided in two main classes based on their time-course. First, estrogens via binding to estrogen receptors regulate the transcription of a variety of genes involved primarily in neurotransmission. These neurochemical effects ultimately result in the activation of male copulatory behavior after a latency of a few days. Correlatively, testosterone and its aromatized metabolites increase the transcription of the aromatase mRNA resulting in an increased concentration and activity of the enzyme that actually precedes behavioral activation. Second, recent studies with quail demonstrate that brain aromatase activity (AA) can also be modulated within minutes by phosphorylation processes regulated by changes in intracellular calcium concentration such as those associated with glutamatergic neurotransmission. The rapid up or down-regulations of brain estrogen concentration presumably resulting from these changes in AA affect, by non-genomic mechanisms with relatively short latencies (frequency increases or decreases respectively within 10–15 min), the expression of male sexual behavior in quail and also in rodents. Brain estrogens thus affect behavior on different time-scales by genomic and non-genomic mechanisms similar to those of a hormone or a neurotransmitter.
copulatory behavior; appetitive sexual behavior; sexual learning; rhythmic contractions of the cloacal gland sphincter; medial preoptic area; non genomic effects of steroids; aromatase; Japanese quail - estrogens
We previously identified cyclin B1-specific T cells and antibodies in cancer patients with cyclin B1+ tumors and also in some healthy individuals. We also demonstrated that these responses may be important in cancer immunosurveillance by showing that vaccination against cyclin B1 prevents growth of transplantable cyclin B1+ tumors in mice. Constitutive overexpression of cyclin B1 was determined to correlate with the lack of p53 function. This allowed us to use p53−/− mice as a model that better approximates human disease. p53−/− mice spontaneously develop cyclin B1+ tumors. At 5–6 weeks of age, when the mice were still healthy with no evidence of tumor, they received the cyclin B1 vaccine and were then observed for tumor growth. We demonstrate that cyclin B1 vaccination can delay spontaneous cyclin B1+ tumor growth and increases median survival of tumor bearing p53−/− mice.
cancer vaccines; immunosurveillance; mouse model
Interferon α2b (IFN-α2b) at high dosage is critical to the reversal of signaling defects in T cells of melanoma patients, and to the durable effector (α DC1) polarization of dendritic cells. These immunoregulatory effects appear to be uniquely achieved with levels of IFN-α only attainable in vivo using the high-dose regimen of IFN-α2b (HDI). Three US cooperative group studies have evaluated the benefit of HDI as an adjuvant therapy for high-risk melanoma. All have demonstrated significant and durable reduction in the frequency of relapse, while the first and third trials have demonstrated significant improvements in the fractions of patients surviving compared with observation (E1684) or with a ganglioside vaccine (GMK, E1694). A meta-analysis of 13 randomized trials evaluating adjuvant IFN therapy has now also demonstrated significant benefits for IFN in terms of RFS and OS. Research of IFN-α in melanoma is now focused on identifying prognostic markers of outcome and predictors of therapeutic response.
melanoma; interferon-α; adjuvant; neoadjuvant
Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR). Altered GR function in depression has been demonstrated by neuroendocrine challenge tests that reliably reveal reduced GR sensitivity as manifested by nonsuppression of cortisol following dexamethasone administration in vivo and lack of immune suppression following administration of glucocorticoids in vitro. Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform. Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase, which is associated with reduced GR translocation, and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-κB (NF-κB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-κB nuclear interactions. Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.
glucocorticoids; cytokines; mood; cell signaling; inflammation; glucocorticoid; NF-κB; p38 MAPK; glucocorticoid insensitivity
It is proposed that the pre-cellular stage of biological evolution unraveled within networks of inorganic compartments that harbored a diverse mix of virus-like genetic elements. This stage of evolution might comprise the Last Universal Cellular Ancestor (LUCA) that more appropriately could be denoted Last Universal Cellular Ancestral State (LUCAS). This scenario for the origin of cellular life recapitulates the early ideas of J. B. S. Haldane sketched in his classic 1928 essay. However, unlike in Haldane’s day, there is now considerable support for this scenario from three major lines of comparative-genomic evidence: i) lack of homology between the core components of the DNA replication systems of the two primary lines of descent of cellular life forms, archaea and bacteria, ii) distinct membrane chemistries and lack of homology between the enzymes of lipid biosynthesis in archaea and bacteria, iii) spread of several viral hallmark genes, which encode proteins with key functions in viral replication and morphogenesis, among numerous and extremely diverse groups of viruses, in contrast to their absence in cellular life forms, iv) the extant archaeal and bacterial chromosomes appear to be shaped by accretion of diverse, smaller replicons, suggesting a continuity between the hypothetical, primordial virus stage of life’s evolution and the dynamic prokaryotic world that existed ever since. Under the viral model of pre-cellular evolution, the key components of cells including the replication apparatus, membranes, and molecular complexes involved in membrane transport and translocation originated as components of virus-like entities. The two surviving types of cellular life forms, archaea and bacteria, might have emerged from the LUCAS independently, along with, probably, numerous forms now extinct.
comparative genomics; evolution of cells; evolution of viruses; origin of membranes; viral hallmark genes
Enteropathogenic E. coli (EPEC) are a leading cause of infantile diarrhea in developing countries, resulting in millions of deaths each year. EPEC secrete virulence factors, also called effectors, directly into host intestinal epithelial cells via type three secretion systems. Secreted effectors then affect host signaling pathways to induce several phenotypes, which ultimately lead to disease. Among the over 20 secreted effectors is E. coli secreted protein F (EspF), a 206 amino acid protein believed to be central to EPEC pathogenesis, as it disrupts tight junction structure and function. Although the mechanism by which this occurs is unknown, EspF has recently been found to contain several protein–protein interaction domains that may be involved. We have shown EspF to interact with the endocytic regulators sorting nexin 9 (SNX9) and N-WASP via non-exclusive binding sites. These interactions induce actin polymerization in vitro, and interaction with SNX9 alters its endocytic activity, as EspF induces the formation of tubular vesicles in a manner dependent upon its interaction with SNX9. EspF, therefore, appears to hijack endocytic regulation via SNX9 and possibly N-WASP interaction, to affect an as yet unidentified pathogenic phenotype.
EPEC; EspF; SNX9; tight junction
Our vestibular organs are simultaneously activated by our own actions as well as by stimulation from the external world. The ability to distinguish sensory inputs that are a consequence of our own actions (e.g., vestibular reafference) from those that result from changes in the external world (e.g., vestibular exafference) is essential for perceptual stability and accurate motor control. Recent work in our laboratory has focused on understanding how the brain distinguishes between vestibular reafference and exafference. Single unit recordings were made in alert rhesus monkeys during passive and voluntary (i.e., active) head movements. We found that neurons in the first central stage of vestibular processing (vestibular nuclei) but not the primary vestibular afferents can distinguish between active and passive movements. In order to better understand how neurons differentiate active from passive head motion, we systematically tested neuronal responses to different combinations of passive and active motion resulting from rotation of the head-on-body and/or head-and-body in space. We found that during active movements, a cancellation signal was generated when the activation of proprioceptors matched the motor-generated expectation.
Vestibular nucleus; self-motion; reafference; efference copy; gaze shift; vestibular reflexes; head-unrestrained
Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. It has been of significant interest to elucidate the structure-function relationship of aromatase since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family, and forms an electron-transfer complex with its partner, NADPH-cytochrome P450 reductase. Because of the membrane-bound character and heme-binding instability, no crystal structure of aromatase has been reported so far. Much remains to be investigated, including the 3-dimensional structure of aromatase, interaction between aromatase and reductase, catalytic mechanism of estrogen synthesis by aromatase, and the binding mechanism of aromatase inhibitors. This review will present current knowledge about structural and functional characteristics of aromatase to address unsolved mysteries about this enzyme.
aromatase; aromatase inhibitors; breast cancer; computer modeling; estrogen; NADPH-cytochrome P450 reductase; structure-function studies
To what extent can remaining sensory information and/or sensory biofeedback compensate for loss of vestibular information in controlling postural equilibrium? The primary role of the vestibulospinal system is as a vertical reference for control of the trunk in space, with increasing importance as the surface becomes increasingly unstable. Our studies with patients with bilateral loss of vestibular function show that vision or light touch from a fingertip can substitute as a reference for earth vertical to decrease variability of trunk sway when standing on an unstable surface. However, some patients with bilateral loss compensate better than others and we find that those with more complete loss of bilateral vestibular function compensate better than those with measurable vestibulo-ocular reflexes. In contrast, patients with unilateral vestibular loss who reweight sensory dependence to rely on their remaining unilateral vestibular function show better functional performance than those who do not increase vestibular weighting on an unstable surface. Light touch of <100 grams or auditory biofeedback can be added as a vestibular vertical reference to stabilize trunk sway during stance. Postural ataxia during tandem gait in patients with unilateral vestibular loss is also significantly improved with vibrotactile biofeedback to the trunk, beyond improvements due to practice. Vestibular rehabilitation should focus on decreasing hypermetria, decreasing an over-dependence on surface somatosensory inputs, increasing use of any remaining vestibular function, substituting or adding alternative sensory feedback related to trunk sway, and practicing challenging balance tasks on unstable surfaces.
posture; compensation; adaptation; vestibular loss; rehabilitation
We studied the dynamics and kinematics of saccades in a patient with severe ocular myasthenia before and after treatment with intravenous immunoglobulin (IVIG). Before therapy, horizontal saccades were hypometric, but faster than similar-sized saccades made by normal subjects. During a 5-minute test period, saccades decreased in size (fatigue effect), but remained faster than those of controls. Listing’s plane of the eye with greater ophthalmoplegia was increased in thickness. After IVIG treatment, the range of eye movements improved, but saccades remained faster than those of controls. Also, no fatigue was observed and the thickness of Listing’s plane was reduced towards the normal range. Increased peak velocity, despite progressive hypometria due to fatigue, supports the hypothesis that the pale global extraocular muscle fibers are relatively spared in myasthenia. Involvement of other extraocular muscle fiber types leads to limited range of eye movements and an increase in the thickness of Listing’s plane.
saccades; fatigue; pale extraocular muscle fibers; Listing’s plane
Signal transducer and activator of transcription-3 (STAT-3) is one of six members of a family of transcription factors. It was discovered almost 15 years ago as an acute-phase response factor. This factor has now been associated with inflammation, cellular transformation, survival, proliferation, invasion, angiogenesis, and metastasis of cancer. Various types of carcinogens, radiation, viruses, growth factors, oncogenes, and inflammatory cytokines have been found to activate STAT-3. STAT-3 is constitutively active in most tumor cells but not in normal cells. Phosphorylation of STAT-3 at tyrosine 705 leads to its dimerization, nuclear translocation, DNA binding, and gene transcription. The phosphorylation of STAT-3 at serine 727 may regulate its activity negatively or positively. STAT-3 regulates the expression of genes that mediate survival (survivin, bcl-xl, mcl-1, cellular FLICE-like inhibitory protein), proliferation (c-fos, c-myc, cyclin D1), invasion (matrix metalloproteinase-2), and angiogenesis (vascular endothelial growth factor). STAT-3 activation has also been associated with both chemoresistance and radioresistance. STAT-3 mediates these effects through its collaboration with various other transcription factors, including nuclear factor-κB, hypoxia-inducible factor-1, and peroxisome proliferator activated receptor-γ. Because of its critical role in tumorigenesis, inhibitors of this factor’s activation are being sought for both prevention and therapy of cancer. This has led to identification of small peptides, oligonucleotides, and small molecules as potential STAT-3 inhibitors. Several of these small molecules are chemo-preventive agents derived from plants. This review discusses the intimate relationship between STAT-3, inflammation, and cancer in more detail.
STAT-3; inflammation; cancer; chemoresistance
Rift Valley fever virus (RVFV), which belongs to the genus Phlebovirus, family Bunyaviridae, is a negative-stranded RNA virus carrying a single-stranded, tripartite RNA genome. RVFV is an important zoonotic pathogen transmitted by mosquitoes and causes large outbreaks among ruminants and humans in Africa and the Arabian Peninsula. Human patients develop an acute febrile illness, followed by a fatal hemorrhagic fever, encephalitis or ocular diseases. A viral nonstructural protein, NSs, is a major viral virulence factor. Past studies showed that NSs suppresses the transcription of host mRNAs, including interferon-β mRNAs. Here we demonstrated that the NSs protein induced post-transcriptional downregulation of dsRNA-dependent protein kinase, PKR, to prevent phosphorylation of eIF2α and promoted viral translation in infected cells. These two biological activities of the NSs most probably have a synergistic effect in suppressing host innate immune functions and facilitate efficient viral replication in infected mammalian hosts.
Rift Valley fever virus; PKR; NSs protein; interferon; transcriptional suppression
Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF-related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF1 receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF1 receptors become rapidly desensitized by G protein-coupled receptor kinase (GRK) and β-arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress-induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and β-arrestin binding can shift a G protein-coupled receptor (GPCR) to signal selectively via the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) or Akt pathways independent of G proteins. Also, Epac-dependent CRF1 receptor signaling via the ERK-MAPK pathway has been found to potentiate brain-derived neurotrophic factor (BDNF)-stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and β-arrestin function may be involved in the pathophysiology of stress-induced anxiety and depression.
corticotropin releasing factor, CRF; urocortin 2, UCN2; urocortin 3, UCN3; CRF receptor type 1, CRF1 receptor; CRF receptor type 2, CRF2 receptor; G protein-coupled receptor, GPCR; GPCR kinase, GRK; cyclic 3′,5′-adenosine monophosphate cyclic AMP; extracellular signal-regulated kinase, ERK; mitogen-activated protein kinase, MAPK; brain-derived neurotrophic factor, BDNF
Intestinal electroneutral Na+ absorptive processes account for most intestinal Na+ absorption in the period between meals and also for the great majority of the increase in ileal Na+ absorption that occurs post-prandially. In most diarrheal diseases, there is inhibition of neutral NaCl absorption. Elevated levels of intracellular calcium ([Ca2+]i) are known to inhibit NaCl absorption and involve multiple components of the Ca2+ signaling pathway. The BB Na+/H+ exchanger NHE3 accounts for most of the recognized digestive changes in neutral NaCl absorption, as well as most of the changes in Na+ absorption that occur in diarrheal diseases. Previous studies have examined several aspects of Ca2+ regulation of NHE3 activity. These include phosphorylation, protein trafficking and multi-protein complex formation. In addition, recent studies have demonstrated the role of the NHERF family of PDZ domain–containing proteins in Ca2+ regulation of NHE3 activity, thereby adding a new level of complexity to understanding Ca2+-dependent inhibition of Na+ absorption. In this article, we will review the current understanding of (1) Ca2+ signaling events in intestinal epithelial cells; (2) Ca2+ regulation of intestinal electroneutral sodium absorption, which includes NHE3; and (3) the role of the NHERF family of PDZ domain–containing proteins in Ca2+ regulation of NHE3 activity. We will also present new data on using advanced imaging showing rapid BB NHE3 endocytosis in response to elevated [Ca2+]i.
NHE3; intracellular calcium; NHERF