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

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

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

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

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

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

Staying afloat on Neurath's boat - Heuristics for sequential causal learning

Causal models are key to flexible and efficient exploitation of the environment. However, learning causal structure is hard, with massive spaces of possible models, hard-to-compute marginals and the need to integrate diverse evidence over many instances. We report on two experiments in which participants learnt about probabilistic causal systems involving three and four variables from sequences of interventions. Participants were broadly successful, albeit exhibiting sequential dependence and floundering under high background noise. We capture their behavior with a simple model, based on the “Neurath’s ship” metaphor for scientific progress, that neither maintains a probability distribution, nor computes exact likelihoods

P2X receptor trafficking in neurons is subunit specific

P2X receptors within the CNS mediate excitatory synaptic transmission and also act presynaptically to modulate neurotransmitter release. We have studied the targeting and trafficking of P2X4 and P2X2 receptors heterologously expressed in cultured olfactory bulb neurons. Homomeric P2X4 receptors had a punctate distribution, and many of the puncta colocalized with early endosomes. In contrast, P2X2 receptors were primarily localized at the plasma membrane. By antibody-labeling of surface receptors in living neurons, we showed that P2X4 receptors undergo rapid constitutive internalization and subsequent reinsertion into the plasma membrane, whereas P2X2 receptors were not regulated in such a way. The internalization of P2X4 receptors was dynamin-dependent, and the binding of ATP enhanced the basal rate of retrieval in a Ca2+-independent manner. The presence of the P2X4 subunit in a P2X4/6 heteromer governed the trafficking properties of the receptor. P2X receptors acted presynaptically to enhance the release of glutamate, suggesting that the regulated cycling of P2X4-containing receptors might provide a mechanism for modulation of synaptic transmission