Serotonin Modulates Nicotinic Responses of Adrenal Chromaffin Cells

Vijayaraghavan, Sukumar; Schmid, Herbert; Mapp, Karen S.

doi:10.1111/j.1471-4159.1993.tb03571.x

Cited by 19 publications

(10 citation statements)

References 40 publications

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“…Furthermore, agonists and antagonists of different 5HT receptor subtypes affected the AcCho currents in the same manner, and none of them produced the oscillatory currents characteristic of the activation of 5HT receptors expressed in oocytes (20). Thus, our results show that not only 5HT but also other serotonergic agents act directly on nAcChoRs, much in the same way that 5HT affects the nAcChoRs in other cells (4,16,18).…”

Section: Discussionsupporting

confidence: 61%

“…The IC50 for blockage of AcCho responses by 5HT was -100 ,uM in chick ciliary ganglion neurons (17), C2 myotubes (4), muscle receptors expressed in oocytes (ref. 4 and unpublished results), in bovine chromaffin adrenal cells (18), and in a2,34 neuronal nAcChoRs.…”

Section: Discussionmentioning

confidence: 57%

“…A common feature of the effect of 5HT on both muscle and neuronal cells is the reduction of their responses to AcCho (3,4,(15)(16)(17)(18), and various mechanisms have been proposed to explain the inhibitory action of 5HT on nAcChoRs. For example, it has been suggested that 5HT antagonizes the neuronal nAcChoRs in a competitive manner (16), that it acts through a cAMP-dependent mechanism (19), or that it interacts noncompetitively with AcCho on muscle and neuronal nAcChoRs (4,18). Whatever is the mechanism involved, 5HT has similar potency for inhibiting AcCho currents in a wide variety of cells.…”

Section: Discussionmentioning

confidence: 99%

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Effects of serotonergic agents on neuronal nicotinic acetylcholine receptors.

Garcı́a-Colunga

Miledi

1995

Proc. Natl. Acad. Sci. U.S.A.

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In Xenopus oocytes expressing neuronal nicotinic acetylcholine receptors (nAcChoRs), made up of a2 and f84 subunits, acetylcholine (AcCho) elicited ionic membrane currents (AcCho currents) that were modulated by serotonergic agents. Both agonists and antagonists specific for various serotonin (5-hydroxytryptamine, 5HT) receptor subtypes interacted directly with a2,B4 nAcChoRs: 5HT, (±)-8-hydroxy-2-(di-n-propylamino)tetralin, methysergide, spiperone, and ketanserin reversibly reduced the amplitude of AcCho currents and accelerated their decay. The AcChocurrent time course decayed with two exponential functions. In the presence of 5HT, the fast time constant of current decay (Tf) was not greatly modified, but the slow time constant (Ts) was reduced. With AcCho and 5HT both at 100 ,uM, Ts was reduced from 140 s to 85 s. The order of potency for inhibition of AcCho current amplitudes was (+)-8-hydroxy-2-(di-npropylamino)tetralin > methysergide > spiperone > ketanserin > 5HT. The inhibition was voltage-dependent but the magnitude of the voltage dependence for the different blockers did not correspond to their blocking potency: e.g., the block with spiperone was stronger than with 5HT, but it was less voltage-dependent. Our results suggest that serotonergic agents block neuronal nAcChoRs in a noncompetitive manner, similar to the block of muscle nAcChoR by curare and other substances. These results show that neuronal nAcChoR channels that have been activated by their specific neurotransmitter may be modulated by nonspecific neurotransmitters and their antagonists. These effects may help to better understand brain functions as well as the mode of action of the many serotonergic agents that are used in medical practice.The nicotinic acetylcholine receptor (nAcChoR) is a ligandgated ion channel that opens after it binds the neurotransmitter acetylcholine (AcCho) and that mediates synaptic transmission between nerve and muscle as well as between neurons in the peripheral and central nervous systems. The muscle nAcChoR is a pentameric structure composed of four homologous subunits (a, /3, y or £, and 8) with a stoichiometry of a2P/Y8, whereas nAcChoRs expressed in the peripheral and central nervous systems appear to be composed of two different subunits, one a-like and the other /3-like, with a probable stoichiometry of a2133 (1, 2).The function of nAcChoRs can be modified not only by their specific neurotransmitter and related agonists and antagonists, but also by other neurotransmitters such as serotonin (5-hydroxytryptamine, 5HT) (3, 4) and substance P (5, 6).However, the mechanisms involved in the modulation of nAcChoRs by 5HT are still not well understood. In this paper, we report that neuronal nAcChoRs are affected by serotonergic agents in much the same way that 5HT acts on muscle and Torpedo nAcChoRs (4). These agents act on nAcChoRs in a noncompetitive and voltage-dependent way, probably blocking the open nAcChoR channel complex, as has been proposed for the actions of curare (7, 8), substance P (6), ni...

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Effects of serotonergic agents on neuronal nicotinic acetylcholine receptors.

Garcı́a-Colunga

Miledi

1995

Proc. Natl. Acad. Sci. U.S.A.

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“…This would resemble the effects of hexamethonium, which appears to inhibit muscle AChRs competitively (Rang & Rylett, 1984) but neuronal receptors non-competitively (Charnet et al 1992). However, we have reported that in oocytes expressing the á2â4 neuronal AChR subtype the ACh-current is inhibited by 5_HT in a noncompetitive and voltage-dependent fashion (Garc úa-Colunga & Miledi, 1994, which is similar to the effects of 5_HT on chromaffin cells (Vijayaraghavan et al 1993) and on á7 homomeric AChR (Palma et al 1997).…”

Section: Effects Of Serotonergic Agents On Muscle Achrsmentioning

confidence: 81%

“…Similar mechanisms have been proposed for neuronal AChRs (Akasu & Koketsu, 1986). On the other hand, it has been suggested that 5_HT and other serotonergic agents non-competitively inhibit adult and embryonic muscle, Torpedo and neuronal AChRs, by blocking the ionic channel (Grassi et al 1993;Vijayaraghavan et al 1993;Garc úa-Colunga & Miledi, 1994Palma et al 1996Palma et al , 1997 Garc úa-Colunga et al 1997a,b).…”

Section: Discussionmentioning

confidence: 93%

Blockage of Mouse Muscle Nicotinic Receptors by Serotonergic Compounds

Garcı́a-Colunga¹,

Miledi

1999

Experimental Physiology

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summaryXenopus laevis oocytes were used to analyse the effects of serotonin (5-hydroxytryptamine, 5_HT) and serotonergic agents on ionic currents elicited by the activation of mammalian muscle nicotinic acetylcholine receptors (AChRs). 5_HT as well as other serotonergic agents, such as ketanserin, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), methysergide, spiperone, or fluoxetine alone (up to 1 mÒ), did not elicit membrane currents in Xenopus oocytes expressing AChRs, but they reversibly reduced the current elicited by acetylcholine (ACh-current). Serotonin was applied before, together with or after ACh application, and its effects were examined on desensitizing and non-desensitizing ACh-currents. 5_HT reduced the amplitude and accelerated the desensitization of the desensitizing currents. In contrast, non-desensitizing currents were reduced in amplitude but their time course was not significantly affected. With the same concentration of 5_HT the inhibition was stronger on desensitizing than on non-desensitizing ACh-currents. For example, 100 ìÒ 5_HT reduced the peak of a desensitizing ACh-current to 0·48 ± 0·06 (peak current ratio) and after 40 s the current was reduced to a ratio of 0·25 ± 0·04, whereas a non-desensitizing ACh-current was reduced to a ratio of 0·66 ± 0·01. All the serotonergic agents tested inhibited the ACh-currents rapidly and reversibly, suggesting that they are acting directly on the AChRs. The half-inhibitory concentration, IC50, of 5_HT acting on nondesensitizing currents elicited by 250 nÒ ACh was 247 ± 26 ìÒ and the Hill coefficient was •0·88, suggesting a single site for the interaction of 5_HT with the receptor. It appears that 5_HT inhibits AChRs non-competitively because neither the half-effective concentration of ACh, EC50, for ACh-current nor the Hill coefficient were affected by 5_HT. Furthermore, the extent of inhibition of 5_HT on AChRs did not depend on the nicotinic agonist (suberyldicholine, ACh or nicotine). The inhibition of AChRs by serotonergic agents was voltage-dependent. The electrical distance of the binding site for 5_HT was •0·75, whereas for the other serotonergic agents tested it was •0·22, suggesting that ketanserin, 8-OH-DPAT, methysergide, spiperone and fluoxetine act within the ion channel, but at a site more external than that for 5_HT. These substances inhibited the AChcurrent more potently than 5_HT. We conclude that 5_HT and serotonergic agents inhibit, in a noncompetitive manner, the ACh-current in muscle AChRs by blocking the open receptor-channel complex. Moreover, 5_HT appears to promote the desensitized state of the receptor when the current is elicited by high ACh concentrations. introduction The muscle nicotinic acetylcholine receptor (AChR), a neurotransmitter-gated ion channel, is a member of a gene superfamily that includes GABAA, glycine and 5_HT× receptors (Cockcroft et al. 1995). Structurally, the AChR is a pentamer composed of four different subunits (á, â, ã or å, and ä) with a stoichiometry of áµâãä (Karlin & Akabas, 1995; Unwin, ...

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