Millimeter (MM) wave and microwave frequency radiation produce deeply penetrating effects: the biology and the physics.

Millimeter wave (MM-wave) electromagnetic fields (EMFs) are predicted to not produce penetrating effects in the body. The electric but not magnetic part of MM-EMFs are almost completely absorbed within the outer 1 mm of the body. Rodents are reported to have penetrating MM-wave impacts on the brain, the myocardium, liver, kidney and bone marrow. MM-waves produce electromagnetic sensitivity-like changes in rodent, frog and skate tissues. In humans, MM-waves have penetrating effects including impacts on the brain, producing EEG changes and other neurological/neuropsychiatric changes, increases in apparent electromagnetic hypersensitivity and produce changes on ulcers and cardiac activity. This review focuses on several issues required to understand penetrating effects of MM-waves and microwaves: 1. Electronically generated EMFs are coherent, producing much higher electrical and magnetic forces then do natural incoherent EMFs. 2. The fixed relationship between electrical and magnetic fields found in EMFs in a vacuum or highly permeable medium such as air, predicted by Maxwell's equations, breaks down in other materials. Specifically, MM-wave electrical fields are almost completely absorbed in the outer 1 mm of the body due to the high dielectric constant of biological aqueous phases. However, the magnetic fields are very highly penetrating. 3. Time-varying magnetic fields have central roles in producing highly penetrating effects. The primary mechanism of EMF action is voltage-gated calcium channel (VGCC) activation with the EMFs acting via their forces on the voltage sensor, rather than by depolarization of the plasma membrane. Two distinct mechanisms, an indirect and a direct mechanism, are consistent with and predicted by the physics, to explain penetrating MM-wave VGCC activation via the voltage sensor. Time-varying coherent magnetic fields, as predicted by the Maxwell-Faraday version of Faraday's law of induction, can put forces on ions dissolved in aqueous phases deep within the body, regenerating coherent electric fields which activate the VGCC voltage sensor. In addition, time-varying magnetic fields can directly put forces on the 20 charges in the VGCC voltage sensor. There are three very important findings here which are rarely recognized in the EMF scientific literature: coherence of electronically generated EMFs; the key role of time-varying magnetic fields in generating highly penetrating effects; the key role of both modulating and pure EMF pulses in greatly increasing very short term high level time-variation of magnetic and electric fields. It is probable that genuine safety guidelines must keep nanosecond timescale-variation of coherent electric and magnetic fields below some maximum level in order to produce genuine safety. These findings have important implications with regard to 5G radiation.

Radiofrequency Fields and Calcium Movements Into and Out of Cells.

The recent rollout of 5G telecommunications systems has spawned a renewed call to re-examine the possibility of so-called "non-thermal" harmful effects of radiofrequency (RF) radiation. The possibility of calcium being affected by low-level RF has been the subject of research for nearly 50 years and there have been recent suggestions that voltage-gated calcium channels (VGCCs) are "extraordinarily sensitive" to ambient RF fields. This article examines the feasibility of particularly modulated RF coupling to gating mechanisms in VGCCs and also reviews studies from the literature from the last 50 years for consistency of outcome. We conclude that the currents induced by fields at the ICNIRP guideline limits are many orders of magnitude below those needed to affect gating, and there would need to be a biological mechanism for detection and rectification of the extremely-low-frequency (ELF) modulations, which has not been demonstrated. Overall, experimental studies have not validated that RF affects Ca2+ transport into or out of cells.

Transient Confinement of CaV2.1 Ca2+-Channel Splice Variants Shapes Synaptic Short-Term Plasticity.

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.

Wi-Fi is an important threat to human health.

Repeated Wi-Fi studies show that Wi-Fi causes oxidative stress, sperm/testicular damage, neuropsychiatric effects including EEG changes, apoptosis, cellular DNA damage, endocrine changes, and calcium overload. Each of these effects are also caused by exposures to other microwave frequency EMFs, with each such effect being documented in from 10 to 16 reviews. Therefore, each of these seven EMF effects are established effects of Wi-Fi and of other microwave frequency EMFs. Each of these seven is also produced by downstream effects of the main action of such EMFs, voltage-gated calcium channel (VGCC) activation. While VGCC activation via EMF interaction with the VGCC voltage sensor seems to be the predominant mechanism of action of EMFs, other mechanisms appear to have minor roles. Minor roles include activation of other voltage-gated ion channels, calcium cyclotron resonance and the geomagnetic magnetoreception mechanism. Five properties of non-thermal EMF effects are discussed. These are that pulsed EMFs are, in most cases, more active than are non-pulsed EMFs; artificial EMFs are polarized and such polarized EMFs are much more active than non-polarized EMFs; dose-response curves are non-linear and non-monotone; EMF effects are often cumulative; and EMFs may impact young people more than adults. These general findings and data presented earlier on Wi-Fi effects were used to assess the Foster and Moulder (F&M) review of Wi-Fi. The F&M study claimed that there were seven important studies of Wi-Fi that each showed no effect. However, none of these were Wi-Fi studies, with each differing from genuine Wi-Fi in three distinct ways. F&M could, at most conclude that there was no statistically significant evidence of an effect. The tiny numbers studied in each of these seven F&M-linked studies show that each of them lack power to make any substantive conclusions. In conclusion, there are seven repeatedly found Wi-Fi effects which have also been shown to be caused by other similar EMF exposures. Each of the seven should be considered, therefore, as established effects of Wi-Fi.

Optogenetic manipulation of anatomical re-entry by light-guided generation of a reversible local conduction block.

Aims: Anatomical re-entry is an important mechanism of ventricular tachycardia, characterized by circular electrical propagation in a fixed pathway. It's current investigative and therapeutic approaches are non-biological, rather unspecific (drugs), traumatizing (electrical shocks), or irreversible (ablation). Optogenetics is a new biological technique that allows reversible modulation of electrical function with unmatched spatiotemporal precision using light-gated ion channels. We therefore investigated optogenetic manipulation of anatomical re-entry in ventricular cardiac tissue. Methods and results: Transverse, 150-µm-thick ventricular slices, obtained from neonatal rat hearts, were genetically modified with lentiviral vectors encoding Ca2+-translocating channelrhodopsin (CatCh), a light-gated depolarizing ion channel, or enhanced yellow fluorescent protein (eYFP) as control. Stable anatomical re-entry was induced in both experimental groups. Activation of CatCh was precisely controlled by 470-nm patterned illumination, while the effects on anatomical re-entry were studied by optical voltage mapping. Regional illumination in the pathway of anatomical re-entry resulted in termination of arrhythmic activity only in CatCh-expressing slices by establishing a local and reversible, depolarization-induced conduction block in the illuminated area. Systematic adjustment of the size of the light-exposed area in the re-entrant pathway revealed that re-entry could be terminated by either wave collision or extinction, depending on the depth (transmurality) of illumination. In silico studies implicated source-sink mismatches at the site of subtransmural conduction block as an important factor in re-entry termination. Conclusions: Anatomical re-entry in ventricular tissue can be manipulated by optogenetic induction of a local and reversible conduction block in the re-entrant pathway, allowing effective re-entry termination. These results provide distinctively new mechanistic insight into re-entry termination and a novel perspective for cardiac arrhythmia management.

Effects of electromagnetic field exposure on conduction and concentration of voltage gated calcium channels: A Brownian dynamics study.

A three-dimensional Brownian Dynamics (BD) in combination with electrostatic calculations is employed to specifically study the effects of radiation of high frequency electromagnetic fields on the conduction and concentration profile of calcium ions inside the voltage-gated calcium channels. The electrostatic calculations are performed using COMSOL Multiphysics by considering dielectric interfaces effectively. The simulations are performed for different frequencies and intensities. The simulation results show the variations of conductance, average number of ions and the concentration profiles of ions inside the channels in response to high frequency radiation. The ionic current inside the channel increases in response to high frequency electromagnetic field radiation, and the concentration profiles show that the residency of ions in the channel decreases accordingly.

Microwave frequency electromagnetic fields (EMFs) produce widespread neuropsychiatric effects including depression.

Non-thermal microwave/lower frequency electromagnetic fields (EMFs) act via voltage-gated calcium channel (VGCC) activation. Calcium channel blockers block EMF effects and several types of additional evidence confirm this mechanism. Low intensity microwave EMFs have been proposed to produce neuropsychiatric effects, sometimes called microwave syndrome, and the focus of this review is whether these are indeed well documented and consistent with the known mechanism(s) of action of such EMFs. VGCCs occur in very high densities throughout the nervous system and have near universal roles in release of neurotransmitters and neuroendocrine hormones. Soviet and Western literature shows that much of the impact of non-thermal microwave exposures in experimental animals occurs in the brain and peripheral nervous system, such that nervous system histology and function show diverse and substantial changes. These may be generated through roles of VGCC activation, producing excessive neurotransmitter/neuroendocrine release as well as oxidative/nitrosative stress and other responses. Excessive VGCC activity has been shown from genetic polymorphism studies to have roles in producing neuropsychiatric changes in humans. Two U.S. government reports from the 1970s to 1980s provide evidence for many neuropsychiatric effects of non-thermal microwave EMFs, based on occupational exposure studies. 18 more recent epidemiological studies, provide substantial evidence that microwave EMFs from cell/mobile phone base stations, excessive cell/mobile phone usage and from wireless smart meters can each produce similar patterns of neuropsychiatric effects, with several of these studies showing clear dose-response relationships. Lesser evidence from 6 additional studies suggests that short wave, radio station, occupational and digital TV antenna exposures may produce similar neuropsychiatric effects. Among the more commonly reported changes are sleep disturbance/insomnia, headache, depression/depressive symptoms, fatigue/tiredness, dysesthesia, concentration/attention dysfunction, memory changes, dizziness, irritability, loss of appetite/body weight, restlessness/anxiety, nausea, skin burning/tingling/dermographism and EEG changes. In summary, then, the mechanism of action of microwave EMFs, the role of the VGCCs in the brain, the impact of non-thermal EMFs on the brain, extensive epidemiological studies performed over the past 50 years, and five criteria testing for causality, all collectively show that various non-thermal microwave EMF exposures produce diverse neuropsychiatric effects.

UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes.

Human skin is constantly exposed to solar ultraviolet radiation (UVR), the most prevalent environmental carcinogen. Humans have the unique ability among mammals to respond to UVR by increasing their skin pigmentation, a protective process driven by melanin synthesis in epidermal melanocytes. The molecular mechanisms used by melanocytes to detect and respond to long-wavelength UVR (UVA) are not well understood. We recently identified a UVA phototransduction pathway in melanocytes that is mediated by G protein-coupled receptors and leads to rapid calcium mobilization. Here we report that in human epidermal melanocytes physiological doses of UVR activate a retinal-dependent current mediated by transient receptor potential A1 (TRPA1) ion channels. The TRPA1 photocurrent is UVA-specific and requires G protein and phospholipase C signaling, thus contributing to UVA-induced calcium responses to mediate downstream cellular effects and providing evidence for TRPA1 function in mammalian phototransduction. Remarkably, TRPA1 activation is required for the UVR-induced and retinal-dependent early increase in cellular melanin. Our results show that TRPA1 is essential for a unique extraocular phototransduction pathway in human melanocytes that is activated by physiological doses of UVR and results in early melanin synthesis.

Effects of weak environmental magnetic fields on the spontaneous bioelectrical activity of snail neurons.

We examined the effects of 50-Hz magnetic fields in the range of flux densities relevant to our current environmental exposures on action potential (AP), after-hyperpolarization potential (AHP) and neuronal excitability in neurons of land snails, Helix aspersa. It was shown that when the neurons were exposed to magnetic field at the various flux densities, marked changes in neuronal excitability, AP firing frequency and AHP amplitude were seen. These effects seemed to be related to the intensity, type (single and continuous or repeated and cumulative) and length of exposure (18 or 20 min). The extremely low-frequency (ELF) magnetic field exposures affect the excitability of F1 neuronal cells in a nonmonotonic manner, disrupting their normal characteristic and synchronized firing patterns by interfering with the cell membrane electrophysiological properties. Our results could explain one of the mechanisms and sites of action of ELF magnetic fields. A possible explanation of the inhibitory effects of magnetic fields could be a decrease in Ca(2+) influx through inhibition of voltage-gated Ca(2+) channels. The detailed mechanism of effect, however, needs to be further studied under voltage-clamp conditions.

Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice.

Throughout life, new neurons are continuously generated in the hippocampus, which is therefore a major site of structural plasticity in the adult brain. We recently demonstrated that extremely low-frequency electromagnetic fields (ELFEFs) promote the neuronal differentiation of neural stem cells in vitro by up-regulating Ca(v)1-channel activity. The aim of the present study was to determine whether 50-Hz/1 mT ELFEF stimulation also affects adult hippocampal neurogenesis in vivo, and if so, to identify the molecular mechanisms underlying this action and its functional impact on synaptic plasticity. ELFEF exposure (1 to 7 h/day for 7 days) significantly enhanced neurogenesis in the dentate gyrus (DG) of adult mice, as documented by increased numbers of cells double-labeled for 5-bromo-deoxyuridine (BrdU) and doublecortin. Quantitative RT-PCR analysis of hippocampal extracts revealed significant ELFEF exposure-induced increases in the transcription of pro-neuronal genes (Mash1, NeuroD2, Hes1) and genes encoding Ca(v)1.2 channel α(1C) subunits. Increased expression of NeuroD1, NeuroD2 and Ca(v)1 channels was also documented by Western blot analysis. Immunofluorescence experiments showed that, 30 days after ELFEF stimulation, roughly half of the newly generated immature neurons had survived and become mature dentate granule cells (as shown by their immunoreactivity for both BrdU and NeuN) and were integrated into the granule cell layer of the DG. Electrophysiological experiments demonstrated that the new mature neurons influenced hippocampal synaptic plasticity, as reflected by increased long-term potentiation. Our findings show that ELFEF exposure can be an effective tool for increasing in vivo neurogenesis, and they could lead to the development of novel therapeutic approaches in regenerative medicine.

Modulation of Ca2+ channel current by mu opioid receptors in prefrontal cortex pyramidal neurons in rats.

Our work assesses the effects of mu opioid receptor activation on high-threshold Ca2+/Ba2+ currents in freshly dispersed pyramidal neurons of the medial prefrontal cortex in rats. Application of the specific mu receptor agonist (D-Ala2+, N-Me-Phe4+, Gly5+-ol)-enkephalin (DAMGO) at 1 microM decreased Ca2+ current amplitudes from 0.72 to 0.49 nA. The effect was abolished by naloxone and omega-Conotoxin GVIA. Inhibition was not abolished by strong depolarisation of the cell membrane. In addition, a macroscopic Ba2+ current recorded in cell-attached configuration was inhibited when DAMGO was applied outside the patch pipette. An adenylyl cyclase inhibitor (SQ 22536) and a protein kinase A inhibitor (H-89) decreased Ca2+ current amplitude. Moreover, the inhibitory effect of mu opioid receptors on Ca2+ currents required the activation of protein kinase A. We conclude that activation of mu opioid receptors in medial prefrontal cortex pyramidal neurons inhibits N type Ca2+ channel currents, and that protein kinase A is involved in this transduction pathway.

New theoretical treatment of ion resonance phenomena.

Despite experimental evidence supporting ICR-like interactions in biological systems, to date there is no reasonable theoretical explanation for this phenomenon. The parametric resonance approach introduced by Lednev has enjoyed limited success in predicting the response as a function of the ratio of AC magnetic intensity to that of the DC field, explaining the results in terms of magnetically induced changes in the transition probability of calcium binding states. In the present work, we derive an expression for the velocity of a damped ion with arbitrary q/m under the influence of the Lorentz force. Series solutions to the differential equations reveal transient responses as well as resonance-like terms. One fascinating result is that the expressions for ionic drift velocity include a somewhat similar Bessel function dependence as was previously obtained for the transition probability in parametric resonance. However, in the present work, not only is there an explicit effect due to damping, but the previous Bessel dependence now occurs as a subset of a more general solution, including not only the magnetic field AC/DC ratio as an independent variable, but also the ratio of the cyclotronic frequency Omega to the applied AC frequency omega. In effect, this removes the necessity to explain the ICR interaction as stemming from ion-protein binding sites. We hypothesize that the selectively enhanced drift velocity predicted in this model can explain ICR-like phenomena as resulting from increased interaction probabilities in the vicinity of ion channel gates.

Age-related functional changes of high-voltage-activated calcium channels in different neuronal subtypes of mouse striatum.

By means of whole-cell patch-clamp recordings, we characterized the developmental profile of high-voltage-activated (HVA) calcium (Ca(2+)) channel subtypes in distinct neuronal populations of mouse striatum. Acutely dissociated medium spiny neurons (MSNs) and cholinergic interneurons (ChIs) were recorded from mice at five developmental stages: postnatal-days (PD) 14, 23, 40, 150 and 270. During ageing, total HVA Ca(2+) current recorded from both MSNs and ChIs was unchanged. However, the pharmacological analysis of the differential contribution of HVA Ca(2+) channel subtypes showed a significant rearrangement of each component. In both neuronal subtypes, a large fraction of the total HVA current recorded from PD14 mice was inhibited by the L-type HVA channel blocker nifedipine. This dihydropyridine-sensitive component accounted for nearly 50%, in MSNs, and 35%, in ChIs, of total current at PD14, but its contribution was down-regulated up to 20-25% at 9 months. Likewise, the N-type, omega-conotoxin GVIA-sensitive component decreased from 35% to 40% to about 25% in MSNs and 15% in ChIs. The P-type, omega-agatoxin-sensitive fraction did not show significant changes in both neuronal subtypes, whereas the Q-type, omega-conotoxin MVIIC-sensitive channels did show a significant up-regulation at 9 months. As compared with striatal neurons, we recorded pyramidal neurons dissociated from cortical layers IV-V and found no significant developmental change in the different components of HVA Ca(2+) currents. In conclusion, our data demonstrate a functional reconfiguration of HVA Ca(2+) channels in striatal but not cortical pyramidal neurons during mouse development. Such changes might have profound implications for physiological and pathophysiological processes of the striatum.

Mechanism of permeation in calcium channels activation by applied magnetic fields.

In this paper, a Brownian dynamics model of cell membrane calcium ion channels exposure to ELF magnetic fields has been proposed for the first time. Based on the model, the permeation of calcium channels activation by applied magnetic fields is given here. The number of opened calcium channel is increase with magnetic fields. The currents of calcium ions in the channel in controls and exposure to ELF magnetic fields are almost the same. These results are consistent with experiments. Thus it can be seen that the current of single calcium channel was nearly unaffected by applied magnetic fields, the increased number of opened calcium channel may be the reason of increased intracellular calcium concentration.

Acute exposure to low-level CW and GSM-modulated 900 MHz radiofrequency does not affect Ba 2+ currents through voltage-gated calcium channels in rat cortical neurons.

We have studied the non-thermal effects of radiofrequency (RF) electromagnetic fields (EMFs) on Ba(2+) currents (I Ba 2+) through voltage-gated calcium channels (VGCC), recorded in primary cultures of rat cortical neurons using the patch-clamp technique. To assess whether low-level acute RF field exposure could modify the amplitude and/or the voltage-dependence of I Ba 2+, Petri dishes containing cultured neurons were exposed for 1-3 periods of 90 s to 900 MHz RF-EMF continuous wave (CW) or amplitude-modulated according to global system mobile communication standard (GSM) during whole-cell recording. The specific absorption rates (SARs) were 2 W/kg for CW and 2 W/kg (time average value) for GSM-modulated signals, respectively. The results obtained indicate that single or multiple acute exposures to either CW or GSM-modulated 900 MHz RF-EMFs do not significantly alter the current amplitude or the current-voltage relationship of I Ba 2+, through VGCC.

Designed electromagnetic pulsed therapy: clinical applications.

First reduced to science by Maxwell in 1865, electromagnetic technology as therapy received little interest from basic scientists or clinicians until the 1980s. It now promises applications that include mitigation of inflammation (electrochemistry) and stimulation of classes of genes following onset of illness and injury (electrogenomics). The use of electromagnetism to stop inflammation and restore tissue seems a logical phenomenology, that is, stop the inflammation, then upregulate classes of restorative gene loci to initiate healing. Studies in the fields of MRI and NMR have aided the understanding of cell response to low energy EMF inputs via electromagnetically responsive elements. Understanding protein iterations, that is, how they process information to direct energy, we can maximize technology to aid restorative intervention, a promising step forward over current paradigms of therapy.

Modeling cell dynamics under mobile phone radiation.

Perturbations by pulse-modulated microwave radiation from GSM mobile phones on neuron cell membrane gating and calcium oscillations have been suggested as a possible mechanism underlying activation of brain states and electroencephalographic epiphenomena. As the employ of UMTS phones seems to reveal other symptoms, a unified phenomenological framework is needed. In order to explain possible effects of mobile phone radiation on cell oscillations, GSM and UMTS low-frequency envelopes have been detected, recorded and used as input in cell models. Dynamical systems endowed with contiguous regular and chaotic regimes suitable to produce stochastic resonance can both account for the perturbation of the neuro-electrical activity and even for the low intensity of the signal perceived by high sensitive subjects. Neuron models of this kind can be employed as a reductionist hint for the mentioned phenomenology. The Hindmarsh-Rose model exhibits frequency enhancement and regularization phenomena induced by weak GSM and UMTS. More realistic simulations of cell membrane gating and calcium oscillations have been performed with the help of an adaptation of the Chay-Keizer dynamical system. This scheme can explain the suspected subjective sensitivity to mobile phone signals under the thermal threshold, in terms of cell calcium regularity mechanisms. Concerning the two kinds of emission, the stronger occupation of the ELF band of last generation UMTS phones is compensated by lower power emitted.

A clockwork hypothesis: synaptic release by rod photoreceptors must be regular.

We can see at light intensities much lower than an average of one photon per rod photoreceptor, demonstrating that rods must be able to transmit a signal after absorption of a single photon. However, activation of one rhodopsin molecule (Rh*) hyperpolarizes a mammalian rod by just 1 mV. Based on the properties of the voltage-dependent Ca2+ channel and data on [Ca2+] in the rod synaptic terminal, the 1 mV hyperpolarization should reduce the rate of release of quanta of neurotransmitter by only 20%. If quantal release were Poisson, the distributions of quantal count in the dark and in response to one Rh* would overlap greatly. Depending on the threshold quantal count, the overlap would generate too frequent false positives in the dark, too few true positives in response to one Rh*, or both. Therefore, quantal release must be regular, giving narrower distributions of quantal count that overlap less. We model regular release as an Erlang process, essentially a mechanism that counts many Poisson events before release of a quantum of neurotransmitter. The combination of appropriately narrow distributions of quantal count and a suitable threshold can give few false positives and appropriate (e.g., 35%) efficiency for one Rh*.

Voltage-dependent calcium currents in trigeminal motoneurons of early postnatal rats: modulation by 5-HT receptors.

Trigeminal motoneurons relay the final output signals generated within the oral-motor pattern generating circuit(s) to muscles for execution of various motor patterns. In recent years, these motoneurons were shown to possess voltage dependent nonlinear membrane properties that allow them to actively participate in sculpting their final output. A complete understanding of the factors controlling trigeminal motoneuronal (TMN) discharge during oral-motor activity requires, at a minimum, a detailed understanding of the palette of ion channels responsible for membrane excitability and a determination of whether these ion channels are targets for modulation. Toward that end, we studied in detail the properties of calcium channels in TMNs and their susceptibility to modulation by 5-HT in rat brain slices. We found that based on pharmacological and voltage-dependent properties, high-voltage-activated (HVA) N-type [omega-conotoxin GVIA (omega-CgTX)]-sensitive, and to a lesser extent P/Q-type [omega-agatoxin IVA (omega-Aga IVA)]-sensitive, calcium channels make up the majority of the whole cell calcium current. 5-HT (5.0 microM) decreased HVA current by 31.3 +/- 2.2%, and the majority of this suppression resulted from reduction of current flow through N- and P/Q-type calcium channels. In contrast, 5-HT had no effect on low-voltage-activated (LVA) current amplitude in TMNs. HVA calcium current inhibition was mimicked by 5-CT, a 5-HT1 receptor agonist, and by R(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), a specific 5-HT1A agonist. The effects of 5-HT were blocked by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide (NAN-190) but not by ketanserin, a 5-HT(2/1C) antagonist. Under current clamp, omega-CgTX and 5-HT were most effective in suppressing the mAHP and both increased the spike frequency and input/output gain in response to current injection. Calcium current modulation by 5-HT1A receptors likely is an important mechanism to fine tune the input/output gain of TMNs in response to small incoming synaptic inputs and accounts for some of the previously reported effects of 5-HT on TMN excitability during tonic and burst activity during oral-motor behavior.

The decrease in the presynaptic calcium current is a major cause of short-term depression at a calyx-type synapse.

Repetitive nerve firings cause short-term depression (STD) of release at many synapses. Its underlying mechanism is largely attributed to depletion of a readily releasable vesicle pool (RRP) and a decreased probability of releasing a readily releasable vesicle during an action potential. Which of these two mechanisms is dominant and the mechanism that decreases the release probability remain debated. Here, we report that a decreased release probability is caused by a calcium-induced inhibition of presynaptic calcium channels, particularly P/Q-type channels at the calyx of Held in rat brainstem. This mechanism was the dominant cause of STD in a wide range of stimulation conditions, such as during 2 to 20 action potential-equivalent stimuli (AP-e) at 0.2-30 Hz and after 2 to 20 AP-e at 0.2-100 Hz. Only during > or = 100 Hz AP-e was depletion the dominant mechanism.