Ion channel proteins

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

We do not know whether the interactions between the presynaptic receptors occur on the level of the receptors or on a site beyond the receptor level, e.g. on the level of G proteins, ion channels or other second messengers. Such receptor interactions may explain drug interactions in vivo. They are also of importance for planning in vitro experiments. H3 receptor-mediated effects in superfused slice preparations are frequently small the inhibitory effect on NA and DA release can be increased by simultaneous blockade of the respective autoreceptor. There are even examples of H3 heteroreceptors which could only be identified if the respective autoreceptor was blocked3 12,36. 

Lear JD, Masserman ZR, DeGrado WF (1988) Synthetic amphiphilic peptide models for protein ion channels. Science 240 1177-1181... 

Amantadine Blockage of the M2 protein ion channel and its ability to modulate intracellular pH influenza A 10-30... 

The evidence is compelling that ion channels are direct G-protein effectors. K+ channels are activated by Ga and inhibited by G, whereas the opening of L-type Ca2+ channels is regulated by Gs or G protein [31]. Studies on G-protein-ion channel membrane interactions have shown that G-proteins may have several membrane targets, including more than one type of ionic channels. 

All peptide and protein ion channels, as well as synthetic ion channels, are amphiphilic structures with an outer coat of nonpolar residues and a lining of polar and charged residues.89-97 These attributes are provided in a cooperative fashion by... 

Receptors or enzymes are the preferred dmg targets since binding and enzyme inhibitor assays are standard in a research laboratory, they can be established easily and offer the possibility of automation. Transport proteins, ion channels and transcription factors are less attractive targets for drug screening programs, because automation is costly and not always possible. In addition, the requirement for highly sophisticated equipment and expertise is decisive. 

Calcium has a dual role in the regulation of cell function It carries charge and thus contributes to the changes of membrane potential in excitable cells, and it acts as a biochemical messenger by directly binding to proteins and modifying their functional state. Proteins directly or indirectly affected by calcium are very diverse and include enz mies, cy-toskeletal proteins, ion channels, and transcription factors. 

It is commonly agreed that the signal transduction cascade, which is much less understood, is also of tremendous importance in mediating the effect of psychotropics. Components of this cascade include G proteins, ion channels, second messengers, and protein kinases (Manji et al. 1995). Interindividual and crossethnic variations in the genes coding these proteins likely exist and may also be responsible for the individual variability in drug response observed clinically. 

Keywords Adenylyl cyclase Aminoalkylindole Anandamide Ca Cannabinoid Cyclic AMP Depolarization suppression of inhibition or excitation Desensitization Endocannabinoid G proteins Ion channels Mitogen activated protein kinases Neurotransmission Nitric oxide Serine/threonine kinases Seven-transmembrane spanning receptors Synaptic plasticity Tyrosine kinases... 

Figure 7 Comparison of protein ion channels. Like-shaded areas within each channel are coded by one gene. See text for details.

Alamethicin. The polypeptide alamethicin adds a level of complexity over gramicidin D. Like gramicidin D it forms cation channels through phospholipid bilayers. Unlike gramicidin D, alamethicin exhibits the voltage dependant gating which is characteristic of many protein ion channels. The alamethicin channel only transports cations when the membrane potential is greater than a threshold value (13). Conductance measurements of a phospholipid... 

E.N. Ervin, R. Kawano, R. White, and H.S. White, "Simultaneous alternating and direct current readout of protein ion channel blocking events using glass nanopore membranes," And. Chem., vol. 60, no. 6, pp. 2069-2076, Jan. 2008. 

As an example, we consider the oldest and most powerful method for single-molecule kinetic analysis, the patch clamp analysis of ion-channel proteins. Ion channels regulate the flow of simple ions such as Na, K, and Ca across cell membranes. Movement of ions is equivalent to electrical current, and we have very sensitive methods for detecting electrical currents. If we take a small glass pipette and insert it into a membrane just right, we can electrically insulate the patch of membrane inside the pipette from the rest of the world. If done properly, a single ion channel will be in the patch, and we can watch... 

Lear JD, Wasserman ZR, and Degrade WF. Synthetic Amphiphilic Peptide Models for Protein Ion Channels. Science 1988 240 1177-1181. 

There are many additional fascinating elements to the cell than are mentioned here mitochondria, ribosomes, protein ion channels, and the nuclear envelope, to name but a few. In this chapter, however, we restrict our discussion to the cell membrane, the cytoskeleton, and the nuclear material (e.g., DNA) as these systems are easily amenable to simple descriptions as soft materials. To learn more detail about the variety of other cellular structures not covered here, some extra sources for further reading are suggested at the end of the chapter. After reading this book, I hope that you will start to think about molecular and cell biology in a different light and consider how cellular structures self-assemble as a result of the interplay between intermolecular forces and thermodynamics. 

Bezrukov, S. M. Kasianowicz, J. J. Current noise reveals protonation kinetics and number of ionizable sites in an open protein ion channel. Phys Rev Lett 1993, 70, 2352-2355. 

Amides, bearing both H-bond acceptors (C=0) and donors (NH), play an important role in Namre (e.g., a helices and sheets of peptides and proteins, ion channels), and in technology as structural materials (e.g.. Nylons) [4]. For example, the X-ray crystal structure of the sulfate-binding protein of Salmonella typhimurium shows that the sulfate is bound by seven H-bonds, five of which involve amide NH groups of polypeptides [5]. The pXa of the amide NH is about 12-21 and becomes lower when modified with electron-deficient groups. Consequentiy, amide as an excellent H-bond donor to bind anionic species has attracted much attention of supramo-lecular, biological, and environmental chemists, especially for anion recognition, transport, and pollution remediation [6-11]. 

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