Characterizing signal encoding and transmission in class I and class II neurons via ordinal time-series analysis.

Neurons encode and transmit information in spike sequences. However, despite the effort devoted to understand the encoding and transmission of information, the mechanisms underlying the neuronal encoding are not yet fully understood. Here, we use a nonlinear method of time-series analysis (known as ordinal analysis) to compare the statistics of spike sequences generated by applying an input signal to the neuronal model of Morris-Lecar. In particular, we consider two different regimes for the neurons which lead to two classes of excitability: class I, where the frequency-current curve is continuous and class II, where the frequency-current curve is discontinuous. By applying ordinal analysis to sequences of inter-spike-intervals (ISIs) our goals are (1) to investigate if different neuron types can generate spike sequences which have similar symbolic properties; (2) to get deeper understanding on the effects that electrical (diffusive) and excitatory chemical (i.e., excitatory synapse) couplings have; and (3) to compare, when a small-amplitude periodic signal is applied to one of the neurons, how the signal features (amplitude and frequency) are encoded and transmitted in the generated ISI sequences for both class I and class II type neurons and electrical or chemical couplings. We find that depending on the frequency, specific combinations of neuron/class and coupling-type allow a more effective encoding, or a more effective transmission of the signal.

Identification and Characterization of a Secondary Sodium-Binding Site and the Main Selectivity Determinants in the Human Concentrative Nucleoside Transporter 3.

The family of concentrative Na+/nucleoside cotransporters in humans is constituted by three subtypes, namely, hCNT1, hCNT2, and hCNT3. Besides their different nucleoside selectivity, hCNT1 and hCNT2 have a Na+/nucleoside stoichiometry of 1:1, while for hCNT3 it is 2:1. This distinct stoichiometry of subtype 3 might hint the existence of a secondary sodium-binding site that is not present in the other two subtypes, but to date their three-dimensional structures remain unknown and the residues implicated in Na+ binding are unclear. In this work, we have identified and characterized the Na+ binding sites of hCNT3 by combining molecular modeling and mutagenesis studies. A model of the transporter was obtained by homology modeling, and key residues of two sodium-binding sites were identified and verified with a mutagenesis strategy. The structural model explains the altered sodium-binding properties of the hCNT3C602R polymorphic variant and supports previously generated data identifying the determinant residues of nucleoside selectivity, paving the way to understand how drugs can target this plasma membrane transporter.

Structural Plasticity in Globins: Role of Protein Dynamics in Defining Ligand Migration Pathways.

Globins are a family of proteins characterized by the presence of the heme prosthetic group and involved in variety of biological functions in the cell. Due to their biological relevance and widespread distribution in all kingdoms of life, intense research efforts have been devoted to disclosing the relationships between structural features, protein dynamics, and function. Particular attention has been paid to the impact of differences in amino acid sequence on the topological features of docking sites and cavities and to the influence of conformational flexibility in facilitating the migration of small ligands through these cavities. Often, tunnels are carved in the interior of globins, and ligand exchange is regulated by gating residues. Understanding the subtle intricacies that relate the differences in sequence with the structural and dynamical features of globins with the ultimate aim of rationalizing the thermodynamics and kinetics of ligand binding continues to be a major challenge in the field. Due to the evolution of computational techniques, significant advances into our understanding of these questions have been made. In this review we focus our attention on the analysis of the ligand migration pathways as well as the function of the structural cavities and tunnels in a series of representative globins, emphasizing the synergy between experimental and theoretical approaches to gain a comprehensive knowledge into the molecular mechanisms of this diverse family of proteins.