Calcium Channel Blocker (Quinidine) as a New Approach of Male Contraception: A Review

The intentional avoidance of conception via the using a various strategy, sexual practices, chemicals, drugs or surgical method. A successful contraception was permitting a physical relationship between partners without worrying about an unwanted pregnancy and makes sure a freedom to have children when in demand. The purpose is to attain contraception with a highest confidentiality and a minimum cost and side effects. Even though, the intention to finding a new approach of male contraceptives through targeting ion channels was disturbed by lacking the most molecular basis of channels to effect on sperm function. Recently, there is developing of a new approach push of male contraception, based on targeting specific processes in sperm development, maturation, and function by using quinidine as a one of calcium channel blocker. Consequently depending on previous findings and researches on sperm-specific Ca2+ channels, as new non-hormonal drug targets for male contraception. Keywords: Catsper, Male Fertilely, Contraception, Ca2+ Channel Blocker

Cytotoxic effect of Quinidine on testicular tissues, sperm parameters and Ca2+ level in mice sperms; as an option of male contraception

Recently,  there  is developing  of  a  new  approach  push  of  male  contraception,  based  on  targeting  specific  processes  in  sperm development, maturation, and function by using quinidine as a one of calcium channel blocker.The effect of antimalarial alkaloids Quinidine (QD) investigated in the testicular tissue, Ca2+ level and some sperm parameters in male mice. To evaluate the impact of QD as a Ca2+ channel blocker on Ca2+ level, the sperms are exposed to QD directly at concentration 10 and 50 µm through perfusion apparatus have a multiple connecting tubes which perfuse QD directly to the imaging chamber containing sperms, then the Ca2+ imaging have done by using laser scanning fluorescence microscope. While the effects of QD on the sperm parameters (motility, abnormality and death percentages) observed by incubation sperms in chambers containing QD at 500 µm for 2 hours. The result showed a significant decrease (p<0.05) in sperm motility, with an increase in abnormality and death percentages with reversible recovery after Hanks Solution (HS) wash at pH 7.4.On the other hand the sperms were incubated in QD at concentrations 10, 50 µm from 2 to 14 hours respectively, have no any changes on in these sperm parameters and testicular tissues at these lower concentration of QD. Although the effects were apparent on sperm parameters after incubation with QD at 500 µm for 2 hours. Histology disturbance was significantly increased after incubation of testis tissue for 14 hours with QD at Concentration 500µm as compared to control. The changes caused by QD only recovered on sperm parameters and Ca2+ level after washing the sperm with Hanks solution medium (HS) medium containing 2mM Ca2+ at pH 7.4. So under the exposure to QD, the inhibitory effect on fertility parameters of mouse's sperms are reversible due to Hanks (HS) supplementation, but there is no recovery determined in testicular tissues treated by QD even when it washed by HS supplementation. Keywords: Male Fertility, Testis, Sperms, Calcium Blockers, Male Contraceptio

Fast inactivation of Nav current in rat adrenal chromaffin cells involves two independent inactivation pathways

Voltage-dependent sodium (Nav) current in adrenal chromaffin cells (CCs) is rapidly inactivating and tetrodotoxin (TTX)-sensitive. The fractional availability of CC Nav current has been implicated in regulation of action potential (AP) frequency and the occurrence of slow-wave burst firing. Here, through recordings of Nav current in rat CCs, primarily in adrenal medullary slices, we describe unique inactivation properties of CC Nav inactivation that help define AP firing rates in CCs. The key feature of CC Nav current is that recovery from inactivation, even following brief (5 ms) inactivation steps, exhibits two exponential components of similar amplitude. Various paired pulse protocols show that entry into the fast and slower recovery processes result from largely independent competing inactivation pathways, each of which occurs with similar onset times at depolarizing potentials. Over voltages from -120 to -80 mV, faster recovery varies from ∼3 to 30 ms, while slower recovery varies from ∼50 to 400 ms. With strong depolarization (above -10 mV), the relative entry into slow or fast recovery pathways is similar and independent of voltage. Trains of short depolarizations favor recovery from fast recovery pathways and result in cumulative increases in the slow recovery fraction. Dual-pathway fast inactivation, by promoting use-dependent accumulation in slow recovery pathways, dynamically regulates Nav availability. Consistent with this finding, repetitive AP clamp waveforms at 1-10 Hz frequencies reduce Nav availability 80-90%, depending on holding potential. These results indicate that there are two distinct pathways of fast inactivation, one leading to conventional fast recovery and the other to slower recovery, which together are well-suited to mediate use-dependent changes in Nav availability

Protein Kinase Activation Increases Insulin Secretion by Sensitizing the Secretory Machinery to Ca2+

Glucose and other secretagogues are thought to activate a variety of protein kinases. This study was designed to unravel the sites of action of protein kinase A (PKA) and protein kinase C (PKC) in modulating insulin secretion. By using high time resolution measurements of membrane capacitance and flash photolysis of caged Ca2+, we characterize three kinetically different pools of vesicles in rat pancreatic β-cells, namely, a highly calcium-sensitive pool (HCSP), a readily releasable pool (RRP), and a reserve pool. The size of the HCSP is ∼20 fF under resting conditions, but is dramatically increased by application of either phorbol esters or forskolin. Phorbol esters and forskolin also increase the size of RRP to a lesser extent. The augmenting effect of phorbol esters or forskolin is blocked by various PKC or PKA inhibitors, indicating the involvement of these kinases. The effects of PKC and PKA on the size of the HCSP are not additive, suggesting a convergent mechanism. Using a protocol where membrane depolarization is combined with photorelease of Ca2+, we find that the HCSP is a distinct population of vesicles from those colocalized with Ca2+ channels. We propose that PKA and PKC promote insulin secretion by increasing the number of vesicles that are highly sensitive to Ca2+

Optimal Estimation of Ion-Channel Kinetics from Macroscopic Currents

Markov modeling provides an effective approach for modeling ion channel kinetics. There are several search algorithms for global fitting of macroscopic or single-channel currents across different experimental conditions. Here we present a particle swarm optimization(PSO)-based approach which, when used in combination with golden section search (GSS), can fit macroscopic voltage responses with a high degree of accuracy (errors within 1%) and reasonable amount of calculation time (less than 10 hours for 20 free parameters) on a desktop computer. We also describe a method for initial value estimation of the model parameters, which appears to favor identification of global optimum and can further reduce the computational cost. The PSO-GSS algorithm is applicable for kinetic models of arbitrary topology and size and compatible with common stimulation protocols, which provides a convenient approach for establishing kinetic models at the macroscopic level

A Residue at the Cytoplasmic Entrance of BK-Type Channels Regulating Single-Channel Opening by Its Hydrophobicity

Single large-conductance calcium-activated K+ (BK) channels encoded by the mSlo gene usually have synchronous gating, but a Drosophila dSlo (A2/C2/E2/G5/10) splice variant (dSlo1A) exhibits very flickery openings. To probe this difference in gating, we constructed a mutant I323T. This channel exhibits four subconductance levels similar to those of dSlo1A. Rectification of the single-channel current-voltage relation of I323T decreased as [Ca2+ ]in increased from 10 to 300 μM. Mutagenesis suggests that the hydrophobicity of the residue at the position is important for the wild-type gating; i.e., increasing hydrophobicity prolongs open duration. Molecular dynamics simulation suggests that four hydrophobic pore-lining residues at position 323 of mSlo act cooperatively in a “shutter-like” mechanism gating the permeation of K+ ions. Rate-equilibrium free energy relations analysis shows that the four I323 residues in an mSlo channel have a conformation 65% similar to the closed conformation during gating. Based on these observations, we suggest that the appearance of rectification and substates of BK-type channels arise from a reduction of the cooperativity among these four residues and a lower probability of being open

Lysine-Rich Extracellular Rings Formed by hβ2 Subunits Confer the Outward Rectification of BK Channels

The auxiliary β subunits of large-conductance Ca2+-activated K+ (BK) channels greatly contribute to the diversity of BK (mSlo1 α) channels, which is fundamental to the adequate function in many tissues. Here we describe a functional element of the extracellular segment of hβ2 auxiliary subunits that acts as the positively charged rings to modify the BK channel conductance. Four consecutive lysines of the hβ2 extracellular loop, which reside sufficiently close to the extracellular entryway of the pore, constitute three positively charged rings. These rings can decrease the extracellular K+ concentration and prevent the Charybdotoxin (ChTX) from approaching the extracellular entrance of channels through electrostatic mechanism, leading to the reduction of K+ inflow or the outward rectification of BK channels. Our results demonstrate that the lysine rings formed by the hβ2 auxiliary subunits influences the inward current of BK channels, providing a mechanism by which current can be rapidly diminished during cellular repolarization. Furthermore, this study will be helpful to understand the functional diversity of BK channels contributed by different auxiliary β subunits

A class of chance constrained multiobjective linear programming with birandom coefficients and its application to vendors selection

In this paper, a class of chance constrained multiobjective linear programming model with birandom coefficients is considered for vendor selection problem. Firstly we present a crisp equivalent model for a special case and give a traditional method for crisp model. Then, the technique of birandom simulation is applied to deal with general birandom objective functions and birandom constraints which are usually difficult to be converted into their crisp equivalents. Furthermore, a genetic algorithm based on birandom simulation is designed for solving a birandom multiobjective vendor selection problem. Finally, a real numbers example is given. The paper makes certain contribution in both theoretical and application research related to multiobjective chance constrained programming, as well as in the study of vendor selection problem under uncertain environment.Birandom variable Vendor selection Birandom simulation Genetic algorithm

Mechanically activated ion channels in vacuoles of onion bulb scale parenchyma

International audienceMechanicaly activated ion channels have been reported ni hte vacuoles of red beet parenchyma, where it has been proposed that they participate in osmoregulation. Here, we report that mechanically activated ion channels are also present in the vacuolar membrane of onion bulb scale parenchyma cells