Cation channels, Formation

Inositol 1,4,5-trisphosphate (IP3) receptors are intracellular cation channels. They are expressed in most cells and predominantly within the membranes of the endoplasmic reticulum. They mediate release of Ca2+ from intracellular stores by the many receptors that stimulate IP3 formation. 

The receptors start a second messenger cascade that is initiated by activation of G-proteins in the cell. These, in turn, interact with membrane-bound adenylyl cyclase, which catalyzes the formation of cyclic adenine monophosphate (cAMP) and opening of cAMP-gated cation channels. Depolarization then brings about an action potential, which travels along the axon of the olfactory sensory neuron. Many of the molecular components of this cascade are olfactoiy specific. 

How the hydrophilic a-LTX inserts into lipid membranes and makes cation-permeable pores is not fully known, but an in-depth insight into the mechanisms of channel formation has been gained by combining cryo-EM, biochemical and biophysical studies with toxin mutagenesis. a-LTX pore formation consists of at least three steps toxin tetramerisation, interaction with a specific cell-surface receptor and, finally, membrane insertion. Many experimental procedures can affect some of these steps and thereby prevent or assist channel formation. 

Although Ca2+ only carries a small proportion of currents through cell membrane-inserted a-LTX channels (Hurlbut et al. 1994 Tse and Tse 1999), the influx of Ca2+ through presynaptically-targeted a-LTX channels is most often referred to, because of the well-established link between presynaptic [Ca2+] and neurotransmitter release. There is a wealth of evidence indicating that in conditions favorable to channel formation (e.g., in the presence of divalent cations), influx of extracellular Ca2+ through a-LTX channels is an important aspect of a-LTX action. 

Falnes P0, Madshus IH, Sandvig K, Olsnes S (1992) Replacement of negative by positive charges in the presumed membrane-inserted part of diphtheria toxin B-fragment. Effect on membrane translocation and formation of cation channels. J Biol Chem 267 12284-12290. 

Answer C. Muscarinic receptors present in bronchiolar smooth muscle are of the M3 subtype coupled via Gq proteins to phospholipase C. Activation of this enzyme causes hydrolysis of phosphatidylinositol bisphosphate, with release of IP3 and DAG (the latter activates protein kinase C). Decreased formation of cAMP mediated via a G protein occurs with activation of M2 receptors such as those in the heart. Cation channel opening occurs in response to activation of nicotinic receptors. 

Venturiddin, a highly specific blocker, decreased the channel open probability significantly (Hg.2). Therefore it was likely, that the described cation channels did not arise from contaminations in purified CF CF. Compared to the intact ATP- thase, vdiere 0.5 p.M Venturiddin completely abolish ATP synthesis, the K seemed to be higher. Venturiddin is assumed to bind to subunit m of the channel portion of the AlT-synthase (14). In ei riments with purified subunit m of CF (Fi 5) cation channels with conductance states and gating behaviour similar to CF CF were <%served. These results implied that subunit HI (liberated from CF CF -complexes) was responsible for the formation of cation channels. 

Entropy is the major force for membrane formation. If enough elements of a membrane itself were incorporated in a model cation-channel-former, the normally feeble entropic force might assist the assembly and/or insertion process. If so, then the compound illustrated schematically could be reduced by two covalent linkages to that shown below. It, in turn, could exist in a fully extended conformation as shown. 

---