Faculty Opinions recommendation of Cross-reactivity of acid-sensing ion channel and Na⁺-H⁺ exchanger antagonists with nicotinic acetylcholine receptors.

Rogers, Marc, Lorna M. Colquhoun, James W. Patrick, and John A. Dani. Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors. J. Neurophysiol. 77: 1407–1417, 1997. Ligand-gated nicotinic acetylcholine receptors (nAChRs) and purinergic ATP receptors are often expressed in the same peripheral and central neurons, and ATP and acetylcholine (ACh) are stored together in some synaptic vesicles. Evidence has suggested that nAChRs and ATP receptors are not independent and that some agonists strongly cross-activate and desensitize both receptor types. Rat sympathetic neurons and nAChRs expressed in Xenopus oocytes were studied to determine the significance of the interactions caused by the two agonist types. Current amplitudes induced with separate or combined applications of ATP and nicotine are >90% additive and independent. Half of all neurons tested responded to either ATP or nicotine but not to both, indicating differences in the expression of the two receptors. In neurons that expressed both receptor types, the nAChRs were inhibited by the activity-dependent open-channel blocker chlorisondamine. If the purinergic and nicotinic receptors were significantly dependent and coactivated, then blocking the ion channels opened by a nicotinic agonist should diminish the current activated by a purinergic agonist. That result was not seen; rather, complete open-channel block of nAChRs with chlorisondamine did not significantly alter the amplitude or kinetics of ATP-induced currents in the same neurons. Finally, when cloned nAChR subunits were expressed in oocytes, ATP activated only very small currents compared with the current activated by ACh. For the 13 different nAChR subunit combinations that were studied, ATP (50–500 μM) activated a current that ranged from 0 to 4% of the size of the current activated by 100 μM ACh. In summary, we find that there is little cross reactivity, and nAChRs and purinergic ATP receptors are predominately independent, acting with separable physiological characteristics. Therefore the quantitative Ca2+ flux could be separately determined for nAChRs and ATP receptors. The fraction of total current that is carried by Ca2+ was quantitatively determined by simultaneously measuring the whole cell current and the associated change in intracellular Ca2+ with fura-2. For sympathetic neurons bathed in 2.5 mM Ca2+ at a holding potential of −50 mV, Ca2+ carries 4.8 ± 0.3% (mean ± SE) of the inward current through neuronal nAChRs and 6.5 ± 0.1% of the current through purinergic ATP receptors. In conclusion, activity-dependent Ca2+ influx through predominately independent populations of nAChRs and ATP receptors can produce different intracellular signals at purinergic and cholinergic synapses.

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Heritable Mutations in the Glycine, GABAA/ and Nicotinic Acetylcholine Receptors Provide New Insights into The Ligand-Gated Ion Channel Receptor Superfamily

International Review of Neurobiology ◽

10.1016/s0074-7742(08)60613-3 ◽

1998 ◽

pp. 285-332 ◽

Cited By ~ 22

Author(s):

Behnaz Vafa ◽

Peter R. Schofield

Keyword(s):

Ion Channel ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Nicotinic Acetylcholine

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Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors?

Molecules ◽

10.3390/molecules26082149 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2149

Author(s):

Hugo R. Arias ◽

Katarzyna M. Targowska-Duda ◽

Jesús García-Colunga ◽

Marcelo O. Ortells

Keyword(s):

Ion Channel ◽

Nicotinic Acetylcholine Receptors ◽

Serotonin Reuptake ◽

Acetylcholine Receptors ◽

Selective Serotonin Reuptake Inhibitors ◽

Antidepressant Activity ◽

Serotonin Reuptake Inhibitors ◽

Depression Symptoms ◽

Nicotinic Acetylcholine ◽

Neurotransmitter Systems

It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although their amount is not altered, which is possibly caused by higher endogenous ACh levels, which consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged as possible targets for SSRIs. Studies on dorsal raphe nucleus serotoninergic neurons support the concept that SSRI-induced nAChR inhibition decreases the glutamatergic hyperstimulation observed in stress conditions, which compensates the excessive 5-HT overflow in these neurons and, consequently, ameliorates depression symptoms. At the molecular level, SSRIs inhibit different nAChR subtypes by noncompetitive mechanisms, including ion channel blockade and induction of receptor desensitization, whereas α9α10 nAChRs, which are peripherally expressed and not directly involved in depression, are inhibited by competitive mechanisms. According to the functional and structural results, SSRIs bind within the nAChR ion channel at high-affinity sites that are spread out between serine and valine rings. In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed in different neurotransmitter systems widens the complexity by which these antidepressants may act clinically.

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