Here we review concepts related to an ensemble description of G-protein-coupled receptors. The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor, a prototypical class A GPCR. 19F Nuclear Magnetic Resonance studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping (...) with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation. GPCRs represent a ubiquitous class of transmembrane receptors, responsible for cell signaling and cell homeostasis. Their activation gives rise to conformational changes that allow the receptor to engage downstream partners. Activation can be thought of in terms of a free energy landscape associated with distinct conformers, responsible for the process. Here, the action of ligands is seen to alter this landscape by enabling transitions between key intermediates. (shrink)

G protein‐coupled receptors (GPCRs) constitute the largest family of transmembrane proteins and play a crucial role in regulating diverse cellular functions. They transmit their signaling via binding to intracellular signal transducers and effectors, such as G proteins, GPCR kinases, and β‐arrestins. To influence specific GPCR signaling behaviors, β‐arrestins recruit effectors to form larger signaling complexes. Intriguingly, they facilitate divergent functions for the binding to different receptors. Recent studies relying on advanced structural approaches, novel biosensors and interactome analyses bring (...) us closer to understanding how this specificity is achieved. In this article, we share our hypothesis of how active GPCRs induce specific conformational rearrangements within β‐arrestins to reveal distinct binding interfaces, enabling the recruitment of a subset of effectors to foster specialized signaling complexes. Furthermore, we discuss methods of how to comprehensively assess β‐arrestin conformational states and present the current state of research regarding the functionality of these multifaceted scaffolding proteins. (shrink)

G protein‐coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β‐arrestins. Many agonists of GPCRs promote “biased” responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential “hidden variables” that regulate this behavior. One contributor is “location bias,” which refers to the generation of unique signaling cascades from a given GPCR depending upon (...) the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias. (shrink)

Regulators of G protein signaling (RGS) proteins provide timely termination of G protein‐coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti‐inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS (...) proteins. We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide. (shrink)

Resistance to inhibitors of cholinesterase 8A (Ric‐8A) is a prominent non‐receptor GEF and a chaperone of G protein α‐subunits (Gα). Recent studies shed light on the structure of Ric‐8A, providing insights into the mechanisms underlying its interaction with Gα. Ric‐8A is composed of a core armadillo‐like domain and a flexible C‐terminal tail. Interaction of a conserved concave surface of its core domain with the Gα C‐terminus appears to mediate formation of the initial Ric‐8A/GαGDP intermediate, followed by the formation of a (...) stable nucleotide‐free complex. The latter event involves a large‐scale dislocation of the Gα α5‐helix that produces an extensive primary interface and disrupts the nucleotide‐binding site of Gα. The distal portion of the C‐terminal tail of Ric‐8A forms a smaller secondary interface, which ostensibly binds the switch II region of Gα, facilitating binding of GTP. The two‐site Gα interface of Ric‐8A is distinct from that of GPCRs, and might have evolved to support the chaperone function of Ric‐8A. (shrink)

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF to (...) promote activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur with (...) neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite of (...) the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell‐cell contact or determine epithelial cell polarity which, in a tissue‐specific manner, use intracellular complexes containing FERM domain and actin‐binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 such (...) as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F‐)actin. Morever, cell architectures that promote F‐actin assembly per se also activate YAP by kinase‐dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. (shrink)

Goal‐directed cognition is often discussed in terms of specialized memory structures like the “goal stack.” The goal‐activation model presented here analyzes goal‐directed cognition in terms of the general memory constructs of activation and associative priming. The model embodies three predictive constraints: (1) the interference level, which arises from residual memory for old goals; (1) the strengthening constraint, which makes predictions about time to encode a new goal; and (3) the priming constraint, which makes predictions about the role of (...) cues in retrieving pending goals. These constraints are formulated algebraically and tested through simulation of latency and error data from the Tower of Hanoi, a means‐ends puzzle that depends heavily on suspension and resumption of goals. Implications of the model for understanding intention superiority, postcompletion error, and effects of task interruption are discussed. (shrink)

Ever since their introduction a decade ago, stable introns, a type of noncoding (nc)RNAs, are found to be key players in different important cellular processes acting through regulation of gene expression and feedback loops to maintain cellular homeostasis. Despite being commonly regarded as useless byproducts, recent studies in yeast suggested that stable introns are essential for cell survivability under starvation. In Drosophila, we found that a stable intron, sisR‐1, has a direct effect in regulating mitochondrial dynamics during short‐term fasting and (...) subsequently improved overall oocyte quality. We speculated that the beneficial effects implicated by sisR‐1 is through the activation of mitohormesis, an interesting phenomenon in mitochondrial biology. Mitohormesis is suggested to improve health span and lifespan of cells and organisms, but the involvement of ncRNAs is not well‐documented. Here, we discuss the potential role of sisR‐1 and other ncRNAs in activating mitohormesis and the possible applications in improving cellular and organismal health. (shrink)

In current epistemology, there are two different conceptions of epistemic justification. According to the first genetic conception, a justified belief is a well-formed belief. According to the second defense conception, how the belief is formed is irrelevant to the epistemic justification of the belief. What is important for the justification of the belief is whether the cognitive agent has a defense of the belief in question. ;I construct my own defense account of epistemic justification on the basis of criticizing current (...) defense accounts of epistemic justification. The gist of my account is that I am justified in believing that p only if my belief that p is stored in my memory with a proper causal connection with other psychological states of mine that are adequate grounds for the belief that p. This illuminates an interesting symmetry between the genetic conception of epistemic justification and the defense conception of epistemic justification: in the genetic conception, justified belief is well-formed belief, whereas in a defense conception justified belief is well-stored belief. ;My account is different from current defense theories of epistemic justification in two respects. First, in my account some type of causal relation between the belief and its adequate grounds is crucial for epistemic justification, while other theories deny the relevance of any causal consideration to the justification of beliefs. Their denial is a manifestation of a dogma--the Psychologistic Assumption--deeply rooted in traditional epistemology, such that epistemic justification is wholly a function of psychological states of a cognitive agent. I show that this dogma has to be abandoned. Second, other theories require the explicit representation of the belief about the evidential relation between the belief in question and its adequate grounds. In them, this explicitly represented higher-level belief constitutes the defense of the belief in question. I show that, due to this requirement of explicitly represented higher-level beliefs, current defense accounts run into numerous insuperable problems. Meanwhile, my theory does not face these problems because it does not require higher-level beliefs. (shrink)

Creating focal lesions in primary visual cortex (V1) provides an opportunity to study the role of extra-geniculo-striate pathways for activating extrastriate visual cortex. Previous studies have shown that more than 95% of neurons in macaque area V2 and V3 stop firing after reversibly cooling V1 [1,2,3]. However, no studies on long term recovery in areas V2, V3 following permanent V1 lesions have been reported in the macaque. Here we use macaque fMRI to study area V2, V3 activity patterns from 1 (...) to 22 months after lesioning area V1. We find that visually driven BOLD responses persist inside the V1-lesion projection zones (LPZ) of areas V2 and V3, but are reduced in strength by ,70%, on average, compared to prelesion levels. Monitoring the LPZ activity over time starting one month following the V1 lesion did not reveal systematic changes in BOLD signal amplitude. Surprisingly, the retinotopic organization inside the LPZ of areas V2, V3 remained similar to that of the non-lesioned hemisphere, suggesting that LPZ activation in V2, V3 is not the result of input arising from nearby (non-lesioned) V1 cortex. Electrophysiology recordings of multi-unit activity corroborated the BOLD observations: visually driven multi-unit responses could be elicited inside the V2 LPZ, even when the visual stimulus was entirely contained within the scotoma induced by the V1 lesion. Restricting the stimulus to the intact visual hemi-field produced no significant BOLD modulation inside the V2, V3 LPZs. We conclude that the observed activity patterns are largely mediated by parallel, V1-bypassing, subcortical pathways that can activate areas V2 and V3 in the absence of V1 input. Such pathways may contribute to the behavioral phenomenon of blindsight. (shrink)

The twentieth century has been described as the time of man’s discovery of himself; few have contributed more to this cause than Erik Erikson. _The Clinical Erik Erikson: A psychoanalytic method of engagement and activation_ highlights Erikson’s transforming contributions to the field of psychoanalysis and honors his legacy by providing unpublished clinical case illustrations of his actual psychotherapeutic work. The publication of case material—simple memorable fragments and clinical vignettes— brings the reader into Erikson’s consultation room, providing a portrait of his (...) clinical technique and demonstrating how he actually worked. Stephen Schlein, an authority on Erikson, presents an illuminating account of Erikson’s pioneering work through an exhaustive search of his early monographs on child psychoanalysis, clinical writings, psychotherapeutic case studies, and participation at case conferences at The Austen Riggs Center. Erikson’s writings reveal a psychoanalytic method of extraordinary richness that emphasizes essential ingredients of an interpersonal-relational clinical method and articulates interactional dimensions that have restorative potential. His vision focuses on the relationship, its powerful affects, and a belief that human beings have a potent capacity for real change. This book will be essential reading for psychoanalysts and psychoanalytic psychotherapists. (shrink)

Many psychological scientists and behavioral neuroscientists affirm that “emotion” influences thinking, decision-making, actions, social relationships, well-being, and physical and mental health. Yet there is no consensus on a definition of the word “emotion,” and the present data suggest that it cannot be defined as a unitary concept. Theorists and researchers attribute quite different yet heuristic meanings to “emotion.” They show considerable agreement about emotion activation, functions, and regulation. The central goal of this article is to alert researchers, students, and (...) other consumers of “emotion” research to the multiple meanings or aspects that distinguished scientists attribute to ”emotion,” increase appreciation of its interesting and challenging complexity, and sharpen perspectives on “emotion” and the associated body of literature that is of critical significance to science and society. (shrink)

PDP networks that use nonmonotonic activation functions often produce hidden unit regularities that permit the internal structure of these networks to be interpreted (Berkeley et al., 1995; McCaughan, 1997; Dawson, 1998). In particular, when the responses of hidden units to a set of patterns are graphed using jittered density plots, these plots organize themselves into a set of discrete stripes or bands. In some cases, each band is associated with a local interpretation. On the basis of these observations, Berkeley (...) (2000) has suggested that these bands are both subsymbolic and symbolic in nature, and has used the analysis of one network to support the claim that there are fewer differences between symbols and subsymbols than one might expect. We suggest below that this conclusion is premature. First, in many cases the local interpretation of each band is difficult to relate to the interpretation of a network's response; a more appropriate relationship only emerges when a band associated with one hidden unit is considered in the context of other bands associated with other hidden units (i.e., interpretations of distributed representations are more useful than interpretations of local representations). Second, the content that a band designates to an external observer (i.e., the interpretation assigned to a band by the researcher) can be quite different from the content that a band designates to the output units of the network itself.. We use two different network simulations – including the one described by Berkeley (2000) – to illustrate these points. We conclude that current evidence involving interpretations of nonmonotonic PDP networks actually illustrates the differences between symbolic and subsymbolic processing. (shrink)

A proximal mechanism is proposed whereby early crying helps maintain ideal levels of brain activation during the first three postnatal months. The proposal is consonant with both animal and human infant literatures, and new data are presented in its support.

Two meta-analyses of pharmacological research are presented, demonstrating that psychoactive drugs have consistent effects on EEG and sleep outside of their effects on REM sleep, and demonstrating that drugs other than those affecting sleep neurotransmitter systems and REM sleep can also alter reported nightmare occurrence. These data suggest that the neurobiology data terrain outside activation-synthesis may include sleep and dream electrophysiology, cognitive reports of dreaming, effects of alterations in consciousness on dreaming, immunology and host defense, and clinical therapies for (...) sleep disorders. (shrink)