Serotonin and beyond-a tribute to Manfred Göthert (1939-2019)

Abstract

Manfred Göthert, who had served Naunyn-Schmiedeberg's Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca²⁺ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT₃ receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT₃ receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT_1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT_1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today's pharmacology.

Keywords: 5-HT receptor mutants; 5-HT3 receptor structure and function; AMPA receptors; Mode of action of ethanol; Mode of action of anesthetics; Mode of action of gabapentinoids; NMDA receptors; Presynaptic receptors; Voltage-dependent cation channels; nACh receptors.

Fig. 1

Manfred Göthert and his colleagues of the Institute of Pharmacology and Toxicology, University of Bonn. From left: Martin Barann (inset), Dieter Abbo Kalbhen, Karlfried Karzel, Ivar von Kügelgen, Kurt Racké, Gerhard J. Molderings, Manfred Göthert, Eberhard Schlicker, Michael Brüss, Klaus Fink, Markus Kathmann, and Heinz Bönisch. The photograph was taken on October 29, 2002 in front of the main door of the old institute building in Bonn-Poppelsdorf, Reuterstr. 2b

Fig. 2

Manfred Göthert and some colleagues. From left, first line: Jorge Gonçalves, Manfred Göthert, and Daniel Moura; second line: Mark Geyer, Daniel Hoyer, Ewan Mylecharane, David Nelson, Stephanie Watts, and Richard Green. The photograph was taken on occasion of the 1st EPHAR Serotonin Satellite Meeting in Porto (Portugal) in July 2004 organized by the International Society for Serotonin Research (formerly The Serotonin Club). Note that Moura (Molderings et al. 1993) and Hoyer (e.g., Engel et al. 1986) have cooperated with Manfred Göthert

Fig. 3

Inhibitory and facilitatory presynaptic heteroreceptors on serotoninergic neurones in rat brain cortex slices identified by Manfred Göthert. a The inhibitory effect of five transmitters or mediators leading to inhibition of the electrically (3 Hz) evoked ³H-5-HT release (the receptors are given in parentheses). The curves were re-drawn from Schlicker et al. (1991)—neuropeptide Y; Schlicker et al. (1987b)—prostaglandin E₂; Göthert et al. (1983a)—noradrenaline; Schlicker et al. (1988b)—histamine; Schlicker et al. (1984a)—GABA. b Glutamate and the prototypical agonists at the three ionotropic glutamate receptors (AMPA, kainate, NMDA) facilitate ³H-5-HT release. Re-drawn from Fink et al. (1995b). In both panels, SEM values and statistics are not shown. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate

Fig. 4

a Genomic organization of the human 5-HT_3A receptor gene (HTR3A) with exons (indicated by numbers), localization of the Cys-loop (cystein bond within the N-terminal region) and the four transmembrane regions (TM1-TM4), and the organization of the long (HTR3AL) and of the truncated (HTR3AT) splice variant. b The corresponding protein structure and the two naturally occurring 5-HT_3A receptor variants Arg344His and Pro391Arg due to single-nucleotide polymorphisms of the HTR3A gene. c The protein structures of the human 5-HT₃ receptor subtypes. UTR, untranslated region. All these variants and subtypes have been examined by Manfred Göthert (see text)

Fig. 5

Schematic diagram of a human metabotropic 5-HT receptor in which amino acid exchanges and their position in naturally occurring variants of the 5-HT_1A, 5-HT_1B, 5-HT_2C, and 5-HT₇ receptor are indicated. Manfred Göthert has explored all shown variants (see text)

Fig. 6

Effect of ethanol and ifenprodil on the NMDA-evoked release of various transmitters from rat cerebral cortex and/or striatal slices. a and b The concentration-response curves (CRCs, SEM values not shown). The negative logarithms of the concentrations causing the half-maximum effect, i.e. an inhibition by 50% (ethanol, pIC_50%) and by 20% (ifenprodil, pIC_20%), were correlated with each other as shown in c, yielding a correlation coefficient close to 1. This suggests that ethanol acts on NMDA receptors containing an N2B subunit which is inhibited by ifenprodil in noradrenergic, serotoninergic, and GABAergic neurones. Closed circles, cortical slices preincubated with ³H-noradrenaline; closed squares, cortical slices, ³H-5-HT; closed rhomboids, cortical slices, ³H-GABA; open circles, striatal slices, ³H-dopamine; open triangles, striatal slices, ³H-choline; open squares, striatal slices, ³H-5-HT (CRCs not shown); open rhomboids, striatal slices ³H-GABA (CRCs not shown). Re-drawn from Fink and Göthert (1996). d The structure of NMDA receptors (which occur as di-heteromeric or tri-heteromeric tetramers) and the site of action of ifenprodil. GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate

Fig. 7

Chain of events involved in the inhibitory effect of gabapentin on noradrenaline (NA) release in rat brain cortex. Gabapentin inhibits the K⁺-induced a Ca²⁺ influx via P/Q-type (but not N-type) Ca²⁺ channels, b glutamate and aspartate release, and c NA release via AMPA (but not NMDA) receptors. Experiments were performed on slices or synaptosomes (dotted columns) and results are expressed as means ± SEM (*p < 0.05, **p < 0.01, based on the t-test for paired (B) or unpaired (A, C) data). The fact that the inhibitory effect of gabapentin on NA release (C) was not retained in isolated nerve endings (synaptosomes) demonstrates that it is not related to a direct effect on the noradrenergic neurone. The effect of gabapentin occurred in the range of therapeutically relevant plasma concentrations of 10–100 μM. Re-drawn from Fink et al. (2000). The experiments were further elaborated in the study by Fink et al. (2002b), which shows that the mechanisms also occur in human cortical slices and also extend to pregabalin, another gabapentinoid, but not to its enantiomer R-(-)-3-isobutylgaba. The schematic drawing in d shows that gabapentin (and pregabalin) (i) inhibit Ca²⁺ influx into glutamatergic neurones via P/Q-type (Ca_V2.1) voltage-gated Ca²⁺ channels by binding to its α₂δ subunit, subsequently leading to (ii) decreased glutamate release, (iii) reduced activation of excitatory AMPA receptors on noradrenergic neurones, and (iv) eventually to a decrease in NA release. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; EAA, excitatory amino acids; NMDA, N-methyl-D-aspartate

Fig. 8

The many faces of agmatine. Aspects studied by Manfred Göthert are marked with red color

Fig. 9

The ceremony of awarding the title of Doctor honoris causa of the Medical University of Białystok (Poland) to Manfred Göthert (12 December 2003). First line: Barbara Malinowska, Manfred Göthert, and Maciej Kaczmarski. Second line: Włodzimierz Buczko, Edmund Przegaliński, Zbigniew Herman, Jacek Nikliński, and Jan Górski. Note that B. Malinowska and W. Buczko (e.g., Malinowska et al. 1995) and E. Przegaliński (Przegaliński et al. 2005) cooperated with Manfred Göthert

Fig. 10

Milestones in the elucidation of the mode of action of general anesthetics and Manfred Göthert’s contributions (seminal papers are given in the boxes). Manfred Göthert showed that the general anesthetic halothane is a negative allosteric modulator at periperal nACh und 5-HT₃ receptors; in other words, anesthetics have a much more specific effect than suggested by the Meyer-Overton hypothesis. According to Franks and Lieb (1984, 1997), anesthetics inhibit nACh and 5-HT₃ receptors which are also present in the brain (see figure) and NMDA receptors solely occurring in the brain (see figure) and stimulate central GABA_A receptors (see figure). All receptors are ligand-gated ion channels; only the GABA_A receptors (today believed to be the major target of anesthetic action) are inhibitory. Manfred Göthert also showed that ethanol inhibits peripheral nACh and 5-HT₃ receptors at concentrations obtained under moderate intoxication. Simultaneously with, but independent from, Lovinger et al. (1989), he found that ethanol inhibits NMDA receptors at concentrations occurring under social drinking. Note that the action of general anesthetics and ethanol is very selective: E.g., voltage-dependent cation channels (Na_V, Ca_V; see figure) are affected at extremely high concentrations only

Fig. 11

Milestones in the identification of presynaptic receptors and contributions of Manfred Göthert (seminal papers are given in the boxes). The figure shows that he studied the modulation of noradrenaline release from postganglionic sympathetic neurones by 15 types of presynaptic receptors. Activation of ligand-gated ion channels (LGICs), G_q-coupled and G_s-coupled receptors increases noradrenaline release (+; see vesicles fusing with the cell membrane and releasing noradrenaline molecules into the synaptic cleft); activation of G_i/o protein-coupled receptors decreases noradrenaline release (−). Signaling following activation of G protein-coupled receptors as described by Kubista and Boehm (2006). The types of presynaptic receptors studied by Manfred Göthert are given next to the yellow boxes; in the case of the 5-HT₄-R, a parasympathetic neurone is interpolated and the increased release of ACh eventually leads to inhibition of noradrenaline release (for details, see the “Presynaptic serotonin heteroreceptors on noradrenergic neurones” section). On noradrenergic and serotoninergic neurones of the brain, only LGICs and G_i/o protein-coupled presynaptic receptors occur (not shown) and 13 types of presynaptic receptors were identified by Manfred Göthert (see table on the right hand side). Altogether, 23 different types of presynaptic receptors were examined. ACh, acetylcholine; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C

Fig. 12

Milestones in determination of 5-HT₃-R structure and function and some methods and results of the work of Manfred Göthert (seminal papers are given in the boxes)