Developmental switch in the pharmacology of Ca2+ channels coupled to acetylcholine release

doi:10.1016/0896-6273(92)90092-R

Neuron

Volume 8, Issue 4, April 1992, Pages 715-724

https://doi.org/10.1016/0896-6273(92)90092-R Get rights and content

Abstract

The pharmacological specificity of Ca²⁺ channel-secretion coupling in acetylcholine (ACh) and somatostatin (SOM) release was studied in the chick eye choroid neuromuscular junctions and in dissociated ciliary ganglion (CG) neurons. ACh secretion changes in development from stage (St) 40, when release is dihydropyridine (DHP) and partially ω-conotoxin (ω-CgTX) sensitive, to posthatch, when release is insensitive to DH Ps but sensitive to ω-CgTX. St 40 CG neurons cultured with striated muscle have release properties similar to those of St 40 iris and choroid but different from those of St 34 neurons, which are neither DH P nor ω-CgTX sensitive. SOM (also coreleased from posthatch choroid terminals) can inhibit ACh release in both posthatch and St 40 choroids, suggesting that the SOM receptor interacts with both DHP-sensitive and -insensitive channels.

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Somatostatin receptors
2003, Biochimica et Biophysica Acta - Biomembranes
Citation Excerpt :
The inhibitory response to repeated applications of either agent desensitised, with little evidence of cross-desensitisation. By inhibiting varying proportions of L-type and N-type Ca2+ currents, SRIF continues to regulate secretion of acetylcholine in chick neurones at different stages of maturation [241]. According to Toth et al. [242], activation of SRIF receptors endogenous to HEK-293 cells or kappa-opioid receptors—only expressed upon transfection—led to inhibition of Ca2+ currents in alpha-B1-expressing cells.
In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has therefore been acknowledged to be a third endogenous ligand at SRIF receptors.
This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing the characteristic seven-transmembrane-segment (STMS) topography. Years of intensive research have resulted in cloning of five receptor subtypes (sst₁-sst₅), one of which is represented by two splice variants (sst_2A and sst_2B). The individual subtypes, functionally coupled to the effectors of signal transduction, are differentially expressed throughout the mammalian organism, with corresponding differences in physiological impact. It is evident that receptor function, from a physiological point of view, cannot simply be reduced to the accumulated operations of individual receptors. Far from being isolated functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst₂ and sst₅ receptors) in characteristic proportions. In other words, levels of individual receptor subtypes are highly cell-specific and vary with the co-expression of different-ligand receptors. However, the question is how to quantify the relative contributions of individual receptor subtypes to the integration of transduced signals, ultimately the result of collective receptor activity. The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype-selective analogues. Several have become available.
Voltage-gated calcium channels in adult rat inferior colliculus neurons
2003, Neuroscience
The inferior colliculus (IC) plays a key role in the processing of auditory information and is thought to be an important site for genesis of wild running seizures that evolve into tonic–clonic seizures. IC neurons are known to have Ca²⁺ channels but neither their types nor their pharmacological properties have been as yet characterized. Here, we report on biophysical and pharmacological properties of Ca²⁺ channel currents in acutely dissociated neurons of adult rat IC, using electrophysiological and molecular techniques. Ca²⁺ channels were activated by depolarizing pulses from a holding potential of −90 mV in 10 mV increments using 5 mM barium (Ba²⁺) as the charge carrier. Both low (T-type, VA) and high (HVA) threshold Ca²⁺ channel currents that could be blocked by 50 μM cadmium, were recorded. Pharmacological dissection of HVA currents showed that nifedipine (10 μM, L-type channel blocker), ω-conotoxin GVIA (1 μM, N-type channel blocker), and ω-agatoxin TK (30 nM, P-type channel blocker) partially suppressed the current by 21%, 29% and 22%, respectively. Since at higher concentration (200 nM) ω-agatoxin TK also blocks Q-type channels, the data suggest that Q-type Ca²⁺ channels carry approximately 16% of HVA current. The fraction of current (approximately 12%) resistant to the above blockers, which was blocked by 30 μM nickel and inactivated with τ of 15–50 ms, was considered as R-type Ca²⁺ channel current. Consistent with the pharmacological evidences, Western blot analysis using selective Ca²⁺ channel antibodies showed that IC neurons express Ca²⁺ channel α_1A, α_1B, α_1C, α_1D, and α_1E subunits. We conclude that IC neurons express functionally all members of HVA Ca²⁺ channels, but only a subset of these neurons appear to have developed functional LVA channels.
Calcium channels coupled to neurotransmitter release at dually innervated neuromuscular junctions in the newborn rat
2001, Neuroscience
We studied the effect of several calcium channel blockers (ω-Conotoxin-GVIA, 1 and 3 μM; ω-Agatoxin-IVA, 100 nM; Nitrendipine, 1 and 10 μM) on evoked transmitter release at singly and dually innervated endplates of the levator auris longus muscle from three- to six-day-old rats. In dually innervated fibers, a second endplate potential may appear after the first one when we increase the stimulation intensity. The lowest and highest endplate potential amplitudes are designated “small endplate potential” and “large endplate potential”, respectively. The percentage of doubly innervated junctions remains almost constant throughout the age range examined. Nevertheless, the percentage of junctions innervated by three or more terminal axons drops, whereas the singly innervated junctions increase. Therefore, between postnatal days 3 and 6, roughly half the neuromuscular junctions may experience the final process of axonal elimination. The synaptic efficacy of the large endplate potential in dual junctions, measured as the mean amplitude of the synaptic potential and mean quantal content, was the same as in the junctions that had become recently mono-innervated in the same postnatal period. In singly innervated fibers, the endplate potential size was strongly reduced by both the P/Q-type voltage-dependent calcium channel blocker ω-Agatoxin-IVA (79.17±4.02%; P<0.05) and the N-type voltage-dependent calcium channel blocker ω-Conotoxin-GVIA (56.31±7.80%; P<0.05), whereas endplate potential amplitude was not significantly changed by the L-type voltage-dependent calcium channel blocker Nitrendipine. In dually innervated fibers, the P/Q-type voltage-dependent calcium channel blocker ω-Agatoxin-IVA and L-type voltage-dependent calcium channel blocker Nitrendipine increased the size of the small endplate potential (161.29±47.87% and 109.32±11.03%, respectively; P<0.05 in both cases) and reduced the large endplate potential (74.42±15.32% and 70.91±10.04%, respectively; P<0.05 in both cases). The N-type voltage-dependent calcium channel blocker ω-Conotoxin-GVIA significantly increased the small endplate potential in the first few minutes after toxin application (at 10 min: 90.23±17.38%; P<0.05). This increase was not maintained, while the large endplate potential was strongly inhibited (69.25±7.5%; P<0.05).
In conclusion, in the dually innervated endplates of the newborn rat, presynaptic calcium channel types can have different roles in transmitter release from each of the two inputs, which suggests that nerve terminal voltage-dependent calcium channels are involved in neonatal synaptic maturation.
Multiple types of calcium channels mediate transmitter release during functional recovery of botulinum toxin type A-poisoned mouse motor nerve terminals
1999, Neuroscience
The involvement of different types of voltage-dependent calcium channels in nerve-evoked release of neurotransmitter was studied during recovery from neuromuscular paralysis produced by botulinum toxin type A intoxication. For this purpose, a single subcutaneous injection of botulinum toxin (1 IU; dl₅₀) on to the surface of the mouse levator auris longus muscle was performed. The muscles were removed at several time-points after injection (i.e. at one, two, three, four, five, six and 12 weeks). Using electrophysiological techniques, we studied the effect of different types of calcium channel blockers (nitrendipine, ω-conotoxin-GVIA and ω-agatoxin-IVA) on the quantal content of synaptic transmission elicited by nerve stimulation. Morphological analysis using the conventional silver impregnation technique was also made. During the first four weeks after intoxication, sprouts were found at 80% of motor nerve terminals, while at 12 weeks their number was decreased and the nerve terminals were enlarged. The L-type channel blocker nitrendipine (1 μM) inhibited neurotransmitter release by 80% and 30% at two and five weeks, respectively, while no effects were found at later times. The N-type channel blocker ω-conotoxin-GVIA (1 μM) inhibited neurotransmitter release by 50–70% in muscles studied at two to six weeks, respectively, and had no effect 12 weeks after intoxication. The P-type channel blocker ω-agatoxin-IVA (100 nM) strongly reduced nerve-evoked transmitter release (>90%) at all the time-points studied. Identified motor nerve terminals were also sensitive to both nitrendipine and ω-conotoxin-GVIA.
This study shows that multiple voltage-dependent calcium channels were coupled to release during the period of sprouting and consolidation, suggesting that they may be involved in the nerve ending functional recovery process.
Effects of Cd2+, Pb2+ and CH<inf>3</inf>Hg+ on high voltage-activated calcium currents in pheochromocytoma (PC12) cells: Potency, reversibility, interactions with extracellular Ca2+ and mechanisms of block
1998, Toxicology Letters
Effects of the neurotoxic heavy metals Cd²⁺, Pb²⁺ and CH₃Hg⁺ on current carried by Ca²⁺ ions (I_Ca) through high-voltage activated Ca²⁺ channels in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells were examined to characterize possible differences in the mechanism of action of these metals on Ca²⁺ channel function. Specifically, the potency and reversibility of effect on I_Ca by each metal was examined, as well as the relationship between extracellular [Ca²⁺] and potency of block of I_Ca by Cd²⁺ and Pb²⁺. In addition, the effect of each of these metals on Ca²⁺ channels when applied to the intracellular side of the membrane was also examined. When extracellular solution contained 20, 10 or 5 mM Ca²⁺, the estimated IC₅₀ values (total metal concentration) for block of I_Ca were 15, 10, and 6.5 μM for Cd²⁺ and 7.5, 2.0 and 1.1 μM for Pb²⁺, respectively. CH₃Hg⁺ (1–10 μM) blocked I_Ca (20 mM Ca²⁺) in a time- and concentration-dependent manner. When cells were washed with metal-free solutions, block of I_Ca by Cd²⁺ was reversed rapidly, whereas block by Pb²⁺ was reversed only partially, and block of I_Ca by CH₃Hg⁺ was not reversed. When Pb²⁺ and CH₃Hg⁺ treated cells were washed in metal-free solutions containing 50 μM d-penicillamine (DPEN), block of I_Ca by 10 μM Pb²⁺ was rapidly and completely reversed, whereas, block of I_Ca by 5 μM CH₃Hg⁺ was not reversed. Higher concentrations (500 μM) of 2,3-dimercapto-1-propane sulfonic acid (DMPS) did reverse partially the block of I_Ca by 5 and 10 μM CH₃Hg⁺. When Cd²⁺, Pb²⁺ or CH₃Hg⁺ was present in the intracellular solution, Ca²⁺ channel currents were significantly reduced. These results characterize effects of Cd²⁺ on Ca²⁺ channels and demonstrate that Cd²⁺, Pb²⁺ and CH₃Hg⁺ differ in their actions on Ca²⁺ channels.
Ontogeny of the L-type voltage sensitive calcium channels in chick embryo retinospheroids
1997, Developmental Brain Research
The L-type voltage sensitive calcium channels (VSCC) of chick embryo retinospheroids were characterized during the development in vitro. Functionally, the activity of VSCC was characterized by continuously monitoring the changes in the intracellular free Ca²⁺ concentration (Δ[Ca²⁺]_i) with indo-1, in response to 30 mM KCl. The contribution of the L-type VSCC was evaluated using the L-type VSCC antagonist, nitrendipine. We also characterized the binding of [³H]nitrendipine to retinospheroid membranes during development, and determined the K_d and B_max values. We observed that the changes in [Ca²⁺]_i in response to 30 mM KCl increased from 159.46±6.62 nM at 0 days in vitro (DIV) retinospheroids to 704.4±59.9 nM at 14 DIV retinospheroids. Nitrendipine (2 μM) blocked the Δ[Ca²⁺]_i response by approximately 67% in all ages tested. No significant difference in the K_d values for the nitrendipine binding was observed during in vitro development of the retinospheroids. However, the B_max increased from 27.99±1.95 fmol/mg protein in 0 DIV retinospheroids to 131.09±14.24 fmol/mg protein in 14 DIV retinospheroids, supporting the Δ[Ca²⁺]_i results. The results presented suggest that the increase in [Ca²⁺]_i during development was due to an increase in the number of L-type channels. Therefore, the expression of L-type VSCC is developmentally regulated during retinogenesis in vitro and accompanies neuronal maturation, probably regulating the Ca²⁺ input crucial to the onset of important intracellular Ca²⁺-dependent functions.

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Neuron

ArticleDevelopmental switch in the pharmacology of Ca2+ channels coupled to acetylcholine release

Abstract

Dev. Biol.

Trends Neurosci.

Peptides

Dev. Biol.

Dev. Brain Res.

Neuron

Trends Neurosci.

Neuron

Neuron

Neuroscience

Brain Res.

Trends Neurosci.

Brain Res.

Ca++ current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors

J. Neurosci.

Classes of calcium channels in vertebrate cells

Annu. Rev. Physiol.

Presynaptic calcium currents evoking quantal transmission from avian ciliary ganglion neurons

Synapse

Properties of calcium channels isolated with spider toxin, FTX

Ann. NY Acad. Sci.

Enhanced chemosensitivity of chick parasympathetic neurones in co-culture with myotubes

J. Physiol.

Development of inward currents in chick sensory and autonomic neuronal precursor cells in culture

J. Neurosci.

Calcium antagonists inhibit met-enkephalin immunoreactive material release: in vitro and ex vivo experiments

J. Neural Transm.

Opiate and peptide inhibition of transmitter release in parasympathetic nerve terminals

J. Neurosci.

Endogenous modulation of ACh release by SOM and the differential roles of Ca++ channels

J. Neurosci.

Developmental changes in the pharmacology of Ca2+ dependent neurotransmitter release

Ann. NY Acad. Sci.

Dominant role of N-type Ca++ channels in evoked release of norepinephrine from sympathetic neurons

Science

Article
Developmental switch in the pharmacology of Ca²⁺ channels coupled to acetylcholine release

Ca⁺⁺ current in cortical astrocytes: induction by cAMP and neurotransmitters and permissive effect of serum factors

Endogenous modulation of ACh release by SOM and the differential roles of Ca⁺⁺ channels

Developmental changes in the pharmacology of Ca²⁺ dependent neurotransmitter release

Dominant role of N-type Ca⁺⁺ channels in evoked release of norepinephrine from sympathetic neurons