sporter Slc18a3, known as VACht. Upon release, ACh activates two types of receptors: the ionotropic nicotinic (nAChRs) and the metabotropic muscarinic (mAChRs) receptors. The signal is rapidly terminated by the hydrolysis of ACh carried out by the acetylcholine esterase Ache; the resulting choline is up-taken by the high affinity transporter Slc5a7, known as Cht1. Ache is a very fast acting enzyme and Ach clearance occurs in less than a millisecond. The ionotropic nicotinic receptors are part of the Cys-loop ligand-gated ion channel superfamily that form homo- and heteropentamers. The metabotropic muscarinic receptors are G-protein coupled receptors (GPCRs) that are subdivided into two families, depending on the type of G protein to which they couple. The two receptor types derive their names because in addition to the endogenous ACh ligand they can be activated by nicotine, an alkaloid found in tobacco and other plants and by muscarine, a natural product of certain mushrooms. Signaling via nicotinic receptor type is the subject of this synopsis and presented in the diagram [click to see signaling via mAChRs; for an overall view of ACh, click here]. The pentameric nAChRs receptors form a rather heterogenous family of subtypes due to the range of possible combinations of subunits forming the channel. There are nine alpha, four beta and one each of delta, gamma and epsilon subunits represented by Chrna1-7 and Chrna9-10, Chrnb1-4 and Chrnd, Chrng and Chrne, respectively. There are two agonist binding sites in the heteromeric complexes and five in the homomeric ones. The binding sites are hydrophobic pockets at the interface between subunits with a primary or 'plus' and a complementary or 'minus' component; the alpha subunit supplies the primary component (click to see the structure of the pentameric alpha7 ligand binding domain). In heteromeric complexes, the subunits that do not participate in the binding site are called accessory subunits. The mammalian pentamer at the neuromuscular junction (NMJ) has two alpha1, one each of beta1 and delta and, depending on developmental stage, gamma or epsilon subunits; the gamma subunit is present during embryonic development and is replaced by epsilon in adult muscle. The neuronal subtypes are represented by alpha4beta2 or alpha3beta4 heteromers that can have 2 or 3 copies of the alpha subunit, the alpha7 homomers, other combinations found in various central or peripheral areas, and subtypes that are still to be identified. NMJ - the large chemical synapse between motorneurons and skeletal muscle fibers, has been used to investigate the general principles of synapse formation, development and synaptic transmission and to understand the causes of muscular disorders. The localization/clustering of NMJ-nACHr at the postsynaptic membrane, a process referred to as prepatterning, requires the cytoskeletal protein rapsyn (click to see a model of the receptor-rapsyn complex). Prepatterning as well as stabilization of NMJ is dependent upon the muscle specific kinase MuSK whose own activation requires the participation of other proteins. According to the model, agrin (Agrn) released from motorneurons binds the Lrp4 receptor in muscle. Lrp4 interacts with MuSK in the absence of agrin and the interaction may be enhanced by agrin, acting as an allosteric modulator. MuSK activation also requires binding of the adaptor protein Dok7. Activation of NMJ-nAChR leads to membrane depolarization, cation influx, generation of action potential and stimulation of muscle contraction. In other areas, activation of postsynaptic nAChRs promotes the excitation of postganglionic neurons in ANS or mediates plasticity and cognitive functions in the hippocampus. A well established role of nAChRs activation is the modulation of neurotransmitters release from the neurons where they are pre-synaptically expressed. As such, they promote the release of dopamine, glutamine and GABA from dopaminergic, glutaminergic and GABAergic neurons, respectively as well as Ach and others. Opening of activated channels leads to increase in cytosolic Ca2+ concentration directly via Ca2+ permeable nCAhRs such as the monomeric alpha7 or indirectly via activation of voltage-gated Ca2+ channels subsequent to Na+ influx and membrane depolarization promoted by opening of nAChRs. Exocytosis of synaptic vesicles is Ca2+-dependent. Activation of the dopaminergic system mediates the addictive effect of nicotine. Nicotine also increases the number of neuronal nAChRs, as observed in the brain of smokers compared to non-smokers; the effect may be post-translational in nature as there in no change in the mRNA content. The cholinergic system also plays important roles in development and the immune function. Its deregulation has been associated with a range of conditions, including neurodegenerative, depression and schizophrenia and muscular disroders. Exposure to organophosphates, compounds found in pesticides and insecticides, inhibit Ache leading to uncensored activation of both nAChRs and mAChRs. In addition to addiction, nicotine in high amounts can exert harmful toxic effects. To see the ontology report for annotations, Gviewer and download, click here...(less)