Nicotine alters a broad spectrum of behaviors, including attention, arousal, anxiety, and memory. The cellular physiology of nicotine is comparably diverse: nicotine interacts with an array of ionotropic receptors whose gating can lead to direct depolarization of neurons or to an indirect modulation of neuronal excitability by presynaptic facilitation. Furthermore, as many laboratories have shown, the alpha- and beta-type subunits that comprise neuronal nicotinic acetylcholine receptors (nAChRs) are encoded by multiple, homologous genes, yielding at least seven alpha and three beta subunits, distinct in primary sequence. nAChRs that differ in subunit composition differ in pharmacology, conductance, and kinetics as well as in their permeability to and modulation by calcium. We will first discuss recent studies on the biophysics of a special (peculiar?) subset of nAChRs, focusing on heteromeric nAChRs comprised of alpha 4 beta 2 +/- alpha 5 or alpha 7 +/- beta 2 and alpha 5. These nAChR channel subtypes are potently and differentially modulated by changes in intracellular calcium ([Ca]). Thus, the Po, tau o, and desensitization kinetics of alpha 4 beta 2 channels are altered by changes in [Ca]int from 0 to 50 microM; nAChRs that include the alpha 5 subunit are oppositely regulated. Mutagenesis of specific residues within the M1 and M2 domain of alpha 4, beta 2, and alpha 5 suggest a possible Ca binding "pocket." The assembly of functional nAChRs that include alpha 5 and/or alpha 7 and the potential role of these novel heteromeric complexes in presynaptic facilitation will also be presented.
Attempts to mimic synaptic delivery of acetylcholine (ACh) with brief, repetitive pulses of high concentration ACh at synapses of medial habenula (MHN) and interpeduncular nucleus (IPN) neurons in vitro elicited temporally distinct facilitation and inhibition of glutamate secretion via nicotinic and muscarinic ACh receptor-mediated pathways, respectively. ACh-induced nicotinic facilitation was sustained for up to 2 hr, whereas muscarinic inhibition was transient. Prolonged exposure to nicotine inactivated nicotinic receptors selectively, thus decreasing the relative contribution of the facilitatory versus inhibitory influences of ACh. The net effect of ACh in modulating glutamatergic transmission at MHN-IPN synapses may be determined by pre-exposure to nicotine, because the drug appears to switch the balance between the facilitatory and inhibitory actions of ACh.Key words: neuromodulation; glutamate; acetylcholine; nicotine; presynaptic; nicotinic acetylcholine receptors; medial habenula; interpeduncular nucleusThe cholinergic system in the brain has been implicated in a variety of behavioral and cognitive functions, such as working memory, aspects of learning, attention, and arousal. These actions underlie the interaction of the endogenous neurotransmitter ACh with a variety of receptors that modulate neuronal excitability in networks that receive cholinergic afferents (Wainer et al., 1993;Sarter and Bruno, 1997). However, the cellular mechanisms underlying this neuromodulation are poorly understood. Although muscarinic acetylcholine receptors (mAChRs) are renowned for their effects in cortical regions affected in Alzheimer's disease, nicotinic acetylcholine receptors (nAChRs) may also contribute to cholinergic signaling in the normal and aging brain. Nicotine alters a variety of cognitive and behavioral functions through its specific interaction with nAChRs found within the diffuse terminal fields of central cholinergic projections (Woolf, 1991;Levin, 1992). Activation of nAChRs in circuits related to behavioral reinforcement may underlie the renowned effects of nicotine as an addictive drug (Stolerman and Shoaib, 1991;Schelling, 1992;Stolerman and Jarvis, 1995;Rose and Corrigall, 1997;Mansvelder and McGehee, 2000).Nicotinic receptors are found in the cell bodies, dendrites, and within the presynaptic domains of neurons. Recent electrophysiological studies have provided direct evidence that nAChRs mediate synaptic transmission at central synapses (for review, see Jones et al., 1999). In addition, nAChRs are targeted to synaptic terminal and preterminal domains, consistent with demonstrated effects of ACh and nicotine on the release of a wide variety of neurotransmitters (Rapier et al., 1990;Grady et al., 1992;McGehee et al., 1995;Dani and Heinemann, 1996;Gray et al., 1996;McGehee and Role, 1996;Role and Berg, 1996;Wonnacott, 1997;MacDermott et al., 1999).Nicotine interaction with nAChRs facilitates the induction of long-term potentiation of glutamatergic neurotransmission in the hippocampus (Fujii et al., 1999...
When exogenous ACh is loaded into the cytoplasm of cultured amphibian myocytes and fibroblasts, the cells undergo spontaneous quantal ACh secretion, as detected by the appearance of pulsatile membrane currents in Xenopus myocytes which are manipulated into contact with the cells. These currents resemble in many ways the miniature endplate currents (MEPCs) observed at developing neuromuscular synapses formed on these Xenopus myocytes. Analyses of the frequency, amplitude, and time course of these currents suggests similarity in the cellular mechanisms involved in the packaging and secretion of ACh quanta in fibroblasts, myocytes, and developing neurons. The size of the ACh packets released by the non-neuronal cells were found to be very similar to the size of the neuronal ACh quanta, which are thought to result from the exocytotic release of synaptic vesicles. Moreover, the kinetics with which the ACh packets are discharged from all three cell types are comparable, although the speed of secretion in non-neuronal cells is somewhat slower and more irregular. The spontaneous quantal ACh secretion from neurons and myocytes was decreased by reducing cytosolic Ca2+ level and enhanced by activation of protein kinase C with phorbol ester, but secretion from fibroblasts was unaffected by both treatments. The spontaneous secretion from fibroblasts did show some sensitivity to a rise in cytosolic Ca2+ after treatment with a Ca2+ ionophore. These observations support the hypothesis that the basic machinery for transmitter secretion operating in neurons derive from a more ubiquitous mechanism used for constitutive secretion and membrane trafficking in non-neuronal cells, and neuronal differentiation involves expression of additional unique components for the regulation of the spontaneous quantal secretion.
MEPPs. 6. Composite MEPPs with multiple peaks as well as bursts of small MEPPs were often encountered, even during periods of low frequency. They were suggestive of a complete disorganization of quantal events.7. Fast, slow and composite MEPPs were analysed using the computer model. To simulate the entire variety of signals we had to assume that the MEPPs were generated by either synchronized or desynchronized emission of small quantities of transmitter. The typical relationship observed between amplitude and time course in the population of fast MEPPs suggested that the different amounts of transmitter composing a quantum were delivered synchronously close to each other (either at the same spot or at less than 200 nm apart); it is proposed that they acted on overlapping fields of receptors and that their responses summed up in a superadditive manner.8. Computer analysis of the slow-rising MEPPs was of particular interest since their rapid decay phase indicated that the postsynaptic links (cholinesterase and receptors kinetics) were apparently not altered in this subpopulation. More probably their slow and often irregular rate of rise arose from some desynchronization of the release process.9. It is concluded that at the nerve-electroplaque junction evoked transmitter release operates in the form of quanta containing ca 10000 acetylcholine molecules; the quanta activate independent but closely adjacent postsynaptic fields. Each quantum is apparently composed of a preferential number of subunits emitted at the same point, or very close to each other. The subunits are delivered synchronously in the majority of events (fast MEPPs) but subunit desynchronization occasionally occurs (slow-rising and composite MEPPs).
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