MODULATION OF THE CGMP-GATED CHANNEL BY CALCIUM

Calcium acting through calmodulin has been shown to regulate the affinity of cyclic nucleotide-gated channels expressed in cell lines. But is calmodulin the Ca-sensor that normally regulates these channels

Finding fault: causality and counterfactuals in group attributions.

Attributions of responsibility play a critical role in many group interactions. This paper explores the role of causal and counterfactual reasoning in blame attributions in groups. We develop a general framework that builds on the notion of pivotality: an agent is pivotal if she could have changed the group outcome by acting differently. In three experiments we test successive refinements of this notion - whether an agent is pivotal in close possible situations and the number of paths to achieve pivotality. In order to discriminate between potential models, we introduced group tasks with asymmetric structures. Some group members were complements (for the two to contribute to the group outcome it was necessary that both succeed) whereas others were substitutes (for the two to contribute to the group outcome it was sufficient that one succeeds). Across all three experiments we found that people's attributions were sensitive to the number of paths to pivotality. In particular, an agent incurred more blame for a team loss in the presence of a successful complementary peer than in the presence of a successful substitute

Causal Responsibility and Counterfactuals.

How do people attribute responsibility in situations where the contributions of multiple agents combine to produce a joint outcome? The prevalence of over-determination in such cases makes this a difficult problem for counterfactual theories of causal responsibility. In this article, we explore a general framework for assigning responsibility in multiple agent contexts. We draw on the structural model account of actual causation (e.g., Halpern & Pearl, 2005) and its extension to responsibility judgments (Chockler & Halpern, 2004). We review the main theoretical and empirical issues that arise from this literature and propose a novel model of intuitive judgments of responsibility. This model is a function of both pivotality (whether an agent made a difference to the outcome) and criticality (how important the agent is perceived to be for the outcome, before any actions are taken). The model explains empirical results from previous studies and is supported by a new experiment that manipulates both pivotality and criticality. We also discuss possible extensions of this model to deal with a broader range of causal situations. Overall, our approach emphasizes the close interrelations between causality, counterfactuals, and responsibility attributions

Challenging the role of implicit processes in probabilistic category learning

Considerable interest in the hypothesis that different cognitive tasks recruit qualitatively distinct processing systems has led to the proposal of separate explicit (declarative) and implicit (procedural) systems. A popular probabilistic category learning task known as the weather prediction task is said to be ideally suited to examine this distinction because its two versions, '' observation '' and '' feedback,'' are claimed to recruit the declarative and procedural systems, respectively. In two experiments, we found results that were inconsistent with this interpretation. In Experiment 1, a concurrent memory task had a detrimental effect on the implicit (feedback) version of the task. In Experiment 2, participants displayed comparable and accurate insight into the task and their judgment processes in the feedback and observation versions. These findings have important implications for the study of probabilistic category learning in both normal and patient populations

Energetics of Shaker K channels block by inactivation peptides

A synthetic peptide of the NH2-terminal inactivation domain of the ShB channel blocks Shaker channels which have an NH2-terminal deletion and mimics many of the characteristics of the intramolecular inactivation reaction. To investigate the role of electrostatic interactions in both peptide block and the inactivation process we measured the kinetics of block of macroscopic currents recorded from the intact ShB channel, and from ShB delta 6-46 channels in the presence of peptides, at different ionic strengths. The rate of inactivation and the association rate constants (k(on)) for the ShB peptides decreased with increasing ionic strength. k(on) for a more positively charged peptide was more steeply dependent on ionic strength consistent with a simple electrostatic mechanism of enhanced diffusion. This suggests that a rate limiting step in the inactivation process is the diffusion of the NH2-terminal domain towards the pore. The dissociation rates (k(off)) were insensitive to ionic strength. The temperature dependence of k(on) for the ShB peptide was very high, (Q10 = 5.0 +/- 0.58), whereas k(off) was relatively temperature insensitive (Q10 approximately 1.1). The results suggest that at higher temperatures the proportion of time either the peptide or channel spends in the correct conformation for binding is increased. There were two components to the time course of recovery from block by the ShB peptide, indicating two distinct blocked states, one of which has similar kinetics and dependence on external K+ concentration as the inactivated state of ShB. The other is voltage-dependent and at -120 mV is very unstable. Increasing the net charge on the peptide did not increase sensitivity to knock-off by external K+. We propose that the free peptide, having fewer constraints than the tethered NH2-terminal domain binds to a similar site on the channel in at least two different conformations

The trafficking and targeting of P2X receptors

The functional expression of P2X receptors at the plasma membrane is dependent on their trafficking along secretory and endocytic pathways. There are seven P2X receptor subunits, and these differ in their subcellular distributions because they have very different trafficking properties. Some are retained within the endoplasmic reticulum (ER), while others are predominantly at the cell surface or within endosomes and lysosomes. Changes in recruitment of receptors to and from the plasma membrane provides a way of rapidly up- or down-regulating the cellular response to adenosine triphosphate (ATP). An additional layer of regulation is the targeting of these receptors within the membranes of each compartment, which affects their stability, function and the nature of the effector proteins with which they form signaling complexes. The trafficking and targeting of P2X receptors is regulated by their interactions with other proteins and with lipids and we can expect this to vary in a cell-type specific manner and in response to changes in the environment giving rise to differences in receptor activity and function

Interactions of amino terminal domains of Shaker K channels with a pore blocking site studied with synthetic peptides

Synthetic peptides of the five alternative NH2-terminal sequences of Shaker when applied to the cytoplasmic side of ShB channels that have an NH2-terminal deletion (ShB delta 6-46) block the channel with potencies correlated with the rate of inactivation in the corresponding variant. These peptides share no sequence similarity and yet three out of the five have apparent dissociation constants between 2 and 15 microM, suggesting that the specificity requirements for binding are low. To identify the primary structural determinants required for effective block of ShB delta 6-46, we examined the effects of substitutions made to the 20 residue ShB peptide on association and dissociation rates. Nonpolar residues within the peptide appear to be important in stabilizing the binding through hydrophobic interactions. Substitutions to leucine-7 showed there was a clear correlation between hydrophobicity and the dissociation rate constant (koff) with little effect on the association rate constant (kon). Substituting charged residues for hydrophobic residues within the region 4-8 disrupted binding. Within the COOH-terminal half of the peptide, substitutions that increased the net positive charge increased kon with relatively small changes in koff, suggesting the involvement of long-range electrostatic interactions in increasing the effective concentration of the peptide. Neutralizing charged residues produced small changes in koff. Charges within the region 12-20 act equivalently; alterations which conserved net charge produced little effect on either kon or koff. The results are consistent with this region of the peptide having an extended conformation and suggest that when bound this region makes few contacts with the channel protein and remains relatively unconstrained. Analogous mutations within the NH2-terminal domain of the intact ShB channel produced qualitatively similar effects on blocking and unblocking rates

Beyond Covariation: Cues to Causal Structure

Causal induction has two components: learning about the structure of causal models and learning about causal strength and other quantitative parameters. This chapter argues for several interconnected theses. First, people represent causal knowledge qualitatively, in terms of causal structure; quantitative knowledge is derivative. Second, people use a variety of cues to infer causal structure aside from statistical data (e.g. temporal order, intervention, coherence with prior knowledge). Third, once a structural model is hypothesized, subsequent statistical data are used to confirm, refute, or elaborate the model. Fourth, people are limited in the number and complexity of causal models that they can hold in mind to test, but they can separately learn and then integrate simple models, and revise models by adding and removing single links. Finally, current computational models of learning need further development before they can be applied to human learning

Models of probabilistic category learning in Parkinson's disease: Strategy use and the effects of L-dopa

Probabilistic category learning (PCL) has become an increasingly popular paradigm to study the brain bases of learning and memory. It has been argued that PCL relies on procedural habit learning, which is impaired in Parkinson's disease (PD). However, as PD patients were typically tested under medication, it is possible that levodopa (L-dopa) caused impaired performance in PCL. We present formal models of rule-based strategy switching in PCL, to re-analyse the data from [Jahanshahi, M., Wilkinson, L, Gahir, H., Dharminda, A., & Lagnado, D.A., (2009). Medication impairs probabilistic classification learning in Parkinson's disease. Manuscript submitted for publication] comparing PD patients on and off medication (within subjects) to matched controls. Our analysis shows that PD patients followed a similar strategy switch process as controls when off medication, but not when on medication. On medication, PD patients mainly followed a random guessing strategy, with only few switching to the better Single Cue strategies. PD patients on medication and controls made more use of the optimal Multi-Cue strategy. In addition, while controls and PD patients off medication only switched to strategies which did not decrease performance, strategy switches of PD patients on medication were not always directed as such. Finally, results indicated that PD patients on medication responded according to a probability matching strategy indicative of associative learning, while the behaviour of PD patients off medication and controls was consistent with a rule-based hypothesis testing procedure. (C) 2009 Elsevier Inc. All rights reserved