The cytosolic Ca2+ serves an intracellular mediator for many extracellular signals. The receptors coupling via heterotrimeric G proteins to different …Continue reading
Spinal cord injury (SCI) is a devastating condition afflicting over 13,000 people annually in North America and is an important cause of mortality and neurological morbidity1.
Although early pharmacological intervention after SCI with methylprednisolone2,3 or GM-1 ganglioside4 results in modest neurological improvement, the overall impact of these treatments remains minimal. Therefore, novel therapeutic approaches are required to improve the neurological outcome of these patients.
Dendrotoxins are a family of 7 kDa. homologous polypeptides isolated from both green and black mamba venoms (Dendroaspis sp.)1-3. They contain 57-61 amino acid residues in a single chain, crosslinked by three disulfide bridges. Several Dendrotoxins have been isolated and their amino acid sequences completely (see Table 1) , while β- and γ-Dendrotoxin have only been partially sequenced1-4.
Dendrotoxins were first discovered to facilitate the release of acetylcholine at the neuromuscular junction4,5. Later discoveries demonstrated their ability to selectively block some voltage-dependent K+ channels in nerve endings with high affinity2,5.
The voltage-gated Cl– channel (CLC) family in mammals contains at least nine different genes, encoding the Cl– channels CLC-Ka (CLC-K1), …
Important differences in electrophysiological properties have been noted between different regions of the heart. Electrophysiological heterogeneity has also been detected within different parts of a given tissue, such as the ventricular subendocardium, midmyocardium and subepicardium. Although many molecular candidates for native ionic currents have been identified, the molecular basis of most currents is not completely understood. Heterogeneity of channel protein composition might well underlie the differences observed among the properties of ionic currents or the shape of the action potential in different regions of the heart. Techniques such as immunocytochemistry, immunohistochemistry and Western blotting have played an important role in identifying tissue expression of channel proteins as well as their cellular localization. This
The ability of excitable cells to generate rhythmic, spontaneously firing action potentials is called pacemaking. In heart, pacemaking is accomplished by rhythmic discharge of the sinoatrial node (SA node). The firing rate is determined by a specific current slowly depolarizing a membrane to the threshold level, triggering the action potential. The ionic conductance underlying the cardiac pacemaking was identified over 20 years ago and termed If (f for funny)1, 2. At the same time, a similar current was described in neurons and in retina, termed, respectively, Ih (h for hyperpolarization-activated) and Iq (q for queer)2. The unique features of If/Ih/Iq current are: (1) its activation by hyperpolarization; (2) conductance of Na+ and K+ ions (K+/Na+ ~3-4); (3) blocking by low concentration (0.1-5 mM) of extracellular Cs+; (4) enhancement by cyclic AMP
The mechanism of water movement across cell membranes remained unclear until 1992, when the first water specific channel was identified …
An important family of membrane associated guanylate kinase proteins (MAGUK) are abundantly found in brain. They are also called SAP (synapse associated proteins) because of their location at synapses. The four identified members of this family (PSD95, CHAPSYN110, SAP102, SAP97) have three similar domains (PDZ) at N-terminus. At C-terminus, they have one SH3 domain as well as a guanylate kinase-like sequence. PDZ (PSD95-Dlg-Zo-1) domains are found in hundreds of proteins in various cells and tissues. The archetype of the MAGUK family, PSD95, which is found in brain synapses has been widely studied. Its X-ray structure shows a globular protein in which the C- and N-terminus are closed1,2. Studies reported interactions between a C-terminal tripeptide motif of T/SXV of NMDA receptor and PSD953,4,5 or other SAP
Voltage-gated calcium (CaV) channels play a major role in the normal functioning and pathophysiology of neurons and other excitable cells. Their role includes supply of Ca2+ for transmitter release, regulation of excitability by activation of Ca2+-dependent currents and activation of other Ca2+-dependent processes, including control of gene expression. Since Ca2+ entry regulates so many cellular processes, the correct trafficking and localization of CaV channels is of great importance for the normal functioning of cells.
Recently, mutations in a number of genes, causing disease in humans and mice, have been implicated in the context of voltage dependent ion channels and termed
TRP channels are a large family (20 genes) of plasma membrane, non-selective cationic channels that are either specifically or ubiquitously expressed in excitable and non excitable cells. These proteins are divided into three main subfamilies on the basis of sequence homology; TRPC, TRPV and TRPM1 (see Table). Like the KV channel family, the TRP family can also form heteromers consisting of different members of the same subfamily. Their non-selective cationic nature makes them depolarizing agents, while their calcium permeability makes them as transducers leading to [Ca2+]in elevation. However, there are many different gating mechanism and/or modulating agents that activate and inactivate different members of this channel family (for reviews see2,3).