Ion channels research in the post-genomic era.

摘要: Ion channels are integral membrane proteins that catalyze the flux of ions across cell membranes, and play fundamental roles in a wide variety functions throughout body1. Thus, nervous system, various ion concert regulating neuronal excitability, shaping action potentials, tuning firing patterns, controlling transmitter release or synaptic integration. In cardiovascular they control electrical impulse conduction muscle contraction. kidney regulate fluid secretion electrolyte balance; immune drive exocytosis, stimulate mitochondrial metabolism, activate gene expression, promote activation, growth proliferation T cells. Moreover, also act as regulators developmental processes tissue patterning, disruption their function affects morphogenesis flies, fishes, frogs mammals. On other hand, essential pathophysiology diseases, it is therefore not surprising an ever-growing number diseases found to be caused by dysfunction channels. Genetic defects lead severe neurological, cardiac, muscular metabolic disorders, which called 'channelopathies'1. As such, recognized important drug targets. fact, small molecule modulators have been used clinically anti-arrhythmic, anti-hypertensive, anti-epileptic diuretic agents for decades. In this post-genomic era, when genes encoding most deciphered with remaining elusive yet, full exploration channel has become new frontier biological biomedical research. Despite well-known importance, basic structural physiological properties far from being understood, but recently approachable due development technologies, thereby enabling purification, modification, functional analyses. It now clear operate within macromolecular structures signaling complexes whose study presents exceptional challenge scientists. Nowadays, research undergoing exciting times crystal structure determinations, pharmacological targeting spectroscopic studies protein motions. Precisely at these times, there urgent need integrate interplay structural, biophysical, pharmacological, studies. The articles special issue “Ion Channel Research Post-Genomic Era” reflect such effort different aspects experimental conceptual challenge. TRP represent large family more than 30 distinct subtypes, involved sensory transduction, calcium absorption, cone guidance, keratinocyte development, etc. TRP channel-associated channelopathies range like polycystic disease, skeletal dysplasia, familial episodic pain syndrome. understanding how respond stimuli drugs direct clinical therapeutic relevance diseases. APS issue, Zhan et al2 examine TRPM2, acting reactive oxygen species sensor Ca2+-permeable channel, ischemia/reperfusion injury. They discuss recent progress role TRPM2-mediated injury brain, heart kidney, potentials TRPM2 development. Du al3 provide overview TRPP2 its possible (polycystin-2, PKD2) located endoplasmic reticulum, mediates intracellular Ca2+ associated IP3 receptors ryanodine receptors. mutation PKD2 one major cause autosomal dominant disease (ADPKD), abnormalities vasculature complications. He Ma4 focus on TRPC5 cancer. Dysregulation interrupts homeostasis cancer cells, activates pathways related progression, especially chemoresistance. potential target intervention. Tang al5 regulatory Pirt regulates TRPM8 (a nonselective cation activated menthol cold below 25 °C, expressed dorsal roots trigeminal ganglia). demonstrate enhances activity improving conductance, combined PIP2 exhibits synergistic effect TRPM85. KCNQ (Kv7.1-5 KCNQ1-5) comprise voltage-gated K+ heart, stomach, pancreas inner ear. Kv7.1 channels, conjunction auxiliary β subunit KCNE1, generate IKS current crucial repolarization cardiac potentials. Heteromultimeric Kv7.2/7.3 produce characteristically slowly-activating, non-inactivating IM operates subthreshold potential, modulating excitability. Mutations human Kv7.1–7.4 neurological disorders arrhythmias (the long QT syndrome), neonatal epilepsy deafness. Wang Li6 KCNQ system neural circuits, mechanisms implications physiology medicine. present future perspectives novel treatment seizure, stroke, mental illness. Yue al7 show thallium assay IonWorks Barracuda efficient high-throughput screening (HTS) route identifying KCNQ2 openers. discovered 38 activators collection 80 000 compounds, 2 them EC50 values micromolar level7. Along approach, Yu al summarize HTS technology pharmaceutical industry diverse classes types8. More efforts made improve capability automated electrophysiological instruments hERG-related drug-safety screening9. Xie al10 investigated effects 1-alkanols KCNQ1 ethanol, 1-butanol 1-hexanol all inhibit (KCNQ1/KCNE1) currents longer chain causing inhibition, residue (I257) loop between S4 S5 sensitivity closed-state block10. In addition progresses directions multiple described issue. order understand basis pharmacology KATP openers against Li responses inhibitor Na-azide11. Yu12 review general knowledge structure-function relationship P2X al13 BK blockers. Ge Liu14 prevailing hypotheses attributing electrical-resonance membrane. Stoler Fleidervish15 brief axon initial segment (AIS) calpains sources stroke-induced AIS damage. Finally, Weisbrod al16 ionic underlying pacemaker activity. describe latest characterization previously unrecognized SK4 Ca2+-activated conductance By opposing inward during diastolic depolarization, appear automaticity. In conclusion, multidisciplinary embracing fields science, including biology, pharmacology, biophysical approaches, well chemical computational design strategies, providing better channel-related clues treat them. field very promising, we wish gathering would insights into discovery.