Parallel expected improvements for global optimization: summary, bounds and speed-up

Deliverable no. 2.1.1-BThe sequential sampling strategies based on Gaussian processes are widely used for optimization of time consuming simulators. In practice, such computationally demanding problems are solved by increasing number of processing units. This has therefore induced extensions of sampling criteria which consider the framework of parallel calculation. This report further studies expected improvement criteria for parallel and asynchronous computations. A unified parallel asynchronous expected improvement criterion is formulated. Bounds and strategies for comparing criteria values at various design points are discussed. Finally, the impact of the number of available computing units on the performance is empirically investigated

Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties.

At least three genes encode T-type calcium channel alpha(1) subunits, and identification of cDNA transcripts provided evidence that molecular diversity of these channels can be further enhanced by alternative splicing mechanisms, especially for the alpha(1G) subunit (Ca(V)3.1). Using whole-cell patch-clamp procedures, we have investigated the electrophysiological properties of five isoforms of the human alpha(1G) subunit that display a distinct III-IV linker, namely, alpha(1G-a), alpha(1G-b), and alpha(1G-bc), as well as a distinct II-III linker, namely, alpha(1G-ae), alpha(1G-be), as expressed in HEK-293 cells. We report that insertion e within the II-III linker specifically modulates inactivation, steady-state kinetics, and modestly recovery from inactivation, whereas alternative splicing within the III-IV linker affects preferentially kinetics and voltage dependence of activation, as well as deactivation and inactivation. By using voltage-clamp protocols mimicking neuronal activities, such as cerebellar train of action potentials and thalamic low-threshold spike, we describe that inactivation properties of alpha(1G-a) and alpha(1G-ae) isoforms can support channel behaviors reminiscent to those described in native neurons. Altogether, these data demonstrate that expression of distinct variants for the T-type alpha(1G) subunit can account for specific low-voltage-activated currents observed in neuronal tissues

Voltage-dependent calcium channels and cardiac pacemaker activity: From ionic currents to genes

The spontaneous activity of pacemaker cells in the sino-atrial node controls the heart rhythm and rate under physiological conditions. Compared to working myocardial cells, pacemaker cells express a specific array of ionic channels. The functional importance of different ionic channels in the generation and regulation of cardiac automaticity is currently subject of an extensive research effort and has long been controversial. Among families of ionic channels, Ca(2+) channels have been proposed to substantially contribute to pacemaking. Indeed, Ca(2+) channels are robustly expressed in pacemaker cells, and influence the cell beating rate. Furthermore, they are regulated by the activity of the autonomic nervous system in both a positive and negative way. In this manuscript, we will first discuss how the concept of the involvement of Ca(2+) channels in cardiac pacemaking has been proposed and then subsequently developed by the recent advent in the domain of cardiac physiology of gene-targeting techniques. Secondly, we will indicate how the specific profile of Ca(2+) channels expression in pacemaker tissue can help design drugs which selectively regulate the heart rhythm in the absence of concomitant negative inotropism. Finally, we will indicate how the new possibility to assign a specific gene activity to a given ionic channel involved in cardiac pacemaking could implement the current postgenomic research effort in the construction of the cardiac Physiome

T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids

International audienceLipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC 50 ϳ200 nM for N-arachidonoyl 3-OH-␥-aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3.2 steady-state inactivation and persisted during fatty acid amide hydrolase (FAAH) inhibition as well as in cell-free outside-out patch. In contrast, lipoamino acids had weak effects on high-voltage-activated (HVA) Cav1.2 and Cav2.2 calcium currents, on Nav1.7 and Nav1.8 sodium currents, and on anandamide-sensitive TRPV1 and TASK1 currents. Accordingly, lipoamino acids strongly inhibited native Cav3.2 currents in sensory neurons with small effects on sodium and HVA calcium currents. In addition, we demonstrate here that lipoamino acids NAGly and NAGABA-OH produced a strong thermal analgesia and that these effects (but not those of morphine) were abolished in Cav3.2 knockout mice. Collectively, our data revealed lipoamino acids as a family of endogenous T-type channel inhibitors, suggesting that these ligands can modulate multiple cell functions via this newly evidenced regulation

Inactivation determinants in segment IIIS6 of Cav3.1

Low threshold, T-type, Ca2+ channels of the Cav3 family display the fastest inactivation kinetics among all voltage-gated Ca2+ channels. The molecular inactivation determinants of this channel family are largely unknown. Here we investigate whether segment IIIS6 plays a role in Cav3.1 inactivation as observed previously in high voltage-activated Ca2+ channels.Amino acids that are identical in IIIS6 segments of all Ca2+ channel subtypes were mutated to alanine (F1505A, F1506A, N1509A, F1511A, V1512A, F1519A, FV1511/1512AA). Additionally M1510 was mutated to isoleucine and alanine.The kinetic properties of the mutants were analysed with the two-microelectrode voltage-clamp technique after expression in Xenopus oocytes. The time constant for the barium current (IBa) inactivation, τinact, of wild-type channels at −20 mV was 9.5 ± 0.4 ms; the corresponding time constants of the mutants ranged from 9.2 ± 0.4 ms in V1512A to 45.7 ± 5.2 ms (4.8-fold slowing) in M1510I. Recovery at −80 mV was most significantly slowed by V1512A and accelerated by F1511A.We conclude that amino acids M1510, F1511 and V1512 corresponding to previously identified inactivation determinants in IIIS6 of Cav2.1 (Hering et al. 1998) have a significant role in Cav3.1 inactivation. These data suggest common elements in the molecular architecture of the inactivation mechanism in high and low threshold Ca2+ channels

Multiple determinants in voltage-dependent P/Q calcium channels control their retention in the endoplasmic reticulum

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Modulation of slow inactivation in class A Ca2+ channels by β-subunits

β-subunit modulation of slow inactivation of class A calcium (Ca2+) channels was studied with two-microlectrode voltage clamp after expression of the α1A- (BI-2) together with β1a-, β2a-, β3- or β4-subunits in Xenopus oocytes.On- and off-rates of slow inactivation were estimated from the kinetics of recovery from slow inactivation. Ca2+ channels with an α1A/β-subunit composition inducing the slower rate of fast inactivation displayed the faster rate of slow inactivation. The corresponding order of slow inactivation time constants (τonset) was: α1A/β2a, 33 ± 3 s; α1A/β4, 42 ± 4 s; α1A/β1a, 59 ± 4 s; α1A/β3, 67 ± 5 s (n ≥ 7).Recovery of class A Ca2+ channels from slow inactivation was voltage dependent and accelerated at hyperpolarized voltages. At a given holding potential recovery kinetics were not significantly modulated by different β-subunits.Two mutations in segment IIIS6 (IF1612/1613AA) slowed fast inactivation and accelerated the onset of slow inactivation in the resulting mutant (α1A/IF-AA/β3) in a similar manner as coexpression of the β2a-subunit. Recovery from slow inactivation was slightly slowed in the double mutant.Our data suggest that class A Ca2+ channels enter the ‘slow inactivated’ state more willingly from the open than from the ‘fast inactivated’ state. The rate of slow inactivation is, therefore, indirectly modulated by different β-subunits.Fast and slow inactivation in class A Ca2+ channels appears to represent structurally independent conformational changes. Fast inactivation is not a prerequisite for slow inactivation