scholarly journals Intracellular NASPM allows an unambiguous functional measure of GluA2-lacking calcium-permeable AMPA receptor prevalence

2021 ◽  
Author(s):  
Ian D. Coombs ◽  
Cécile Bats ◽  
Craig A. Sexton ◽  
Stuart G. Cull-Candy ◽  
Mark Farrant
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Receptors ◽  
Regulatory Proteins ◽  
Inward Rectification ◽  
Synaptic Current ◽  
Auxiliary Subunits ◽  
Auxiliary Subunit ◽  
Outward Currents ◽  
Voltage Dependent ◽  
Functional Measure

AbstractCalcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits – including transmembrane AMPAR regulatory proteins, cornichons and GSG1L – that are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here we show that inclusion of the spider toxin analogue 1-naphthylacetyl spermine (NASPM) in the intracellular recording solution results in complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, blocks all outward synaptic current. Thus, our results identify an unambiguous functional measure, sensitive solely to changes in CP-AMPAR prevalence.

scholarly journals Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels

2008 ◽  
Vol 295 (2) ◽  
pp. C557-C565 ◽  
Author(s):  
Sriharsha Vemana ◽  
Shilpi Pandey ◽  
H. Peter Larsson
Keyword(s):  
Binding Site ◽  
Physiological Role ◽  
Time Dependent ◽  
Inward Rectification ◽  
Hcn Channels ◽  
Membrane Hyperpolarization ◽  
Outward Currents ◽  
Voltage Dependent ◽  
Hcn1 Channels ◽  
Pore Blocker

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarization that creates time-dependent, inward rectifying currents, gated by the movement of the intrinsic voltage sensor S4. However, inward rectification of the HCN currents is not only observed in the time-dependent HCN currents, but also in the instantaneous HCN tail currents. Inward rectification can also be seen in mutant HCN channels that have mainly time-independent currents ( 5 ). In the present study, we show that intracellular Mg2+ functions as a voltage-dependent blocker of HCN channels, acting to reduce the outward currents. The affinity of HCN channels for Mg2+ is in the physiological range, with Mg2+ binding with an IC50 of 0.53 mM in HCN2 channels and 0.82 mM in HCN1 channels at +50 mV. The effective electrical distance for the Mg2+ binding site was found to be 0.19 for HCN1 channels, suggesting that the binding site is in the pore. Removing a cysteine in the selectivity filter of HCN1 channels reduced the affinity for Mg2+, suggesting that this residue forms part of the binding site deep within the pore. Our results suggest that Mg2+ acts as a voltage-dependent pore blocker and, therefore, reduces outward currents through HCN channels. The pore-blocking action of Mg2+ may play an important physiological role, especially for the slowly gating HCN2 and HCN4 channels. Mg2+ could potentially block outward hyperpolarizing HCN currents at the plateau of action potentials, thus preventing a premature termination of the action potential.

scholarly journals Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits

Physiology ◽  
2010 ◽  
Vol 25 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Susumu Tomita
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Neurological Disorder ◽  
Neural Circuit ◽  
Ionotropic Glutamate Receptors ◽  
Auxiliary Subunits ◽  
The Brain

Glutamate receptors are major excitatory receptors in the brain. Recent findings have established auxiliary subunits of glutamate receptors as critical modulators of synaptic transmission, synaptic plasticity, and neurological disorder. The elucidation of the molecular rules governing glutamate receptors and subunits will improve our understanding of synapses and of neural-circuit regulation in the brain.

scholarly journals Revisiting inward rectification: K ions permeate through Kir2.1 channels during high-affinity block by spermidine

2012 ◽  
Vol 139 (3) ◽  
pp. 245-259 ◽  
Author(s):  
Tai-An Liu ◽  
Hsueh-Kai Chang ◽  
Ru-Chi Shieh
Keyword(s):  
Single Channel ◽  
Outward Current ◽  
Inward Rectification ◽  
Excitable Cells ◽  
High Affinity ◽  
Current State ◽  
Molecular Events ◽  
Zero Current ◽  
Outward Currents ◽  
Voltage Dependent

Outward currents through Kir2.1 channels play crucial roles in controlling the electrical properties of excitable cells, and such currents are subjected to voltage-dependent block by intracellular Mg2+ and polyamines that bind to both high- and low-affinity sites on the channels. Under physiological conditions, high-affinity block is saturated and yet outward Kir2.1 currents can still occur, implying that high-affinity polyamine block cannot completely eliminate outward Kir2.1 currents. However, the underlying molecular mechanism remains unknown. Here, we show that high-affinity spermidine block, rather than completely occluding the single-channel pore, induces a subconducting state in which conductance is 20% that of the fully open channel. In a D172N mutant lacking the high-affinity polyamine-binding site, spermidine does not induce such a substate. However, the kinetics for the transitions between the substate and zero-current state in wild-type channels is the same as that of low-affinity block in the D172N mutant, supporting the notion that these are identical molecular events. Thus, the residual outward current after high-affinity spermidine block is susceptible to low-affinity block, which determines the final amplitude of the outward current. This study provides a detailed insight into the mechanism underlying the emergence of outward Kir2.1 currents regulated by inward rectification attributed to high- and low-affinity polyamine blocks.

scholarly journals Interactions of polyamines with ion channels

1997 ◽  
Vol 325 (2) ◽  
pp. 289-297 ◽  
Author(s):  
Keith WILLIAMS
Keyword(s):  
Ion Channel ◽  
Glutamate Receptors ◽  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Channel Pore ◽  
K Channels ◽  
Polyamine Analogues ◽  
Voltage Dependent ◽  
The Central Nervous System ◽  
And Control

Endogenous polyamines, in particular spermine, have been found to cause block and modulation of a number of types of ion channel. Intracellular spermine is responsible for intrinsic gating and rectification of strong inward rectifier K+ channels by directly plugging the ion channel pore. These K+ channels control the resting membrane potential in both excitable and non-excitable cells, and control the excitability threshold in neurons and muscle cells. Intracellular spermine causes inward rectification at some subtypes of Ca2+-permeable glutamate receptors in the central nervous system, again by plugging the receptor channel pore, and spermine can even permeate the ion channel of these receptors. Extracellular spermine has multiple effects at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including stimulation that increases the size of NMDA receptor currents, and voltage-dependent block. A number of polyamine-conjugated arthropod toxins and synthetic polyamine analogues are potent antagonists of glutamate receptors, and represent new tools with which to study these receptors. Interactions of polyamines with other types of cation channels have been reported. This area of research represents a new biology and a new pharmacology of polyamines.

scholarly journals Transmembrane Auxiliary Subunits of Voltage-dependent Ion Channels

1996 ◽  
Vol 271 (45) ◽  
pp. 27975-27978 ◽  
Author(s):  
Christina A. Gurnett ◽  
Kevin P. Campbell
Keyword(s):  
Ion Channels ◽  
Auxiliary Subunits ◽  
Voltage Dependent

Presynaptic inhibition produced by an identified presynaptic inhibitory neuron. I. Physiological mechanisms

1986 ◽  
Vol 55 (1) ◽  
pp. 113-130 ◽  
Author(s):  
R. Kretz ◽  
E. Shapiro ◽  
E. R. Kandel
Keyword(s):  
Voltage Clamp ◽  
Presynaptic Inhibition ◽  
Inhibitory Neuron ◽  
Outward Current ◽  
Membrane Potentials ◽  
Slow Inward Current ◽  
Synaptic Potential ◽  
Synaptic Current ◽  
Voltage Dependent ◽  
Stimulation Of

We have examined the synaptic conductance mechanisms underlying presynaptic inhibition in Aplysia californica in a circuit in which all the neural elements are identified cells (Fig. 1). L10 makes connections to identified follower cells (RB and left upper quadrant cells, L2-L6). These connections are presynaptically inhibited by stimulating cells of the L32 cluster (4). L32 cells produce a slow inhibitory synaptic potential on L10. This inhibitory synaptic potential is associated with an apparent increased membrane conductance in L10. Both the inhibitory postsynaptic potential (IPSP) and the conductance increase are voltage dependent; the IPSP could not be reversed by hyperpolarizing the membrane potentials to - 120 mV. The hyperpolarization of L10 induced by L32 reduces the transmitter output of L10 and thereby contributes to presynaptic inhibition. However, this hyperpolarization accounts for about 30% of the effect because presynaptic inhibition can still be observed even when the hyperpolarization of L10 by L32 is prevented by voltage clamping. When L10 is voltage clamped, stimulation of L32 produces a slow outward synaptic current associated with an apparent increased conductance. Both the synaptic current and conductance change measured under clamp are voltage dependent, and the outward current could not be reversed. This synaptic current is not mediated by an increase in C1- conductance. It is sensitive to external K+ concentration, especially at hyperpolarized membrane potentials. With L10 under voltage clamp, stimulation of L32 also reduces a slow inward current in L10. This current has time and voltage characteristics similar to those of the Ca2+ current. Presynaptic inhibition is still produced by L32 when L10 is voltage clamped, and transmitter release is elicited by depolarizing voltage-clamp pulses. This component of presynaptic inhibition, which accounts for approximately 70% of the inhibition, appears to be due to a decrease in the Ca2+ current in the presynaptic neuron.

scholarly journals Distinct AMPA-Type Glutamatergic Synapses in Developing Rat CA1 Hippocampus

2010 ◽  
Vol 104 (4) ◽  
pp. 1899-1912 ◽  
Author(s):  
Elizabeth A. Stubblefield ◽  
Tim A. Benke
Keyword(s):  
Pyramidal Neurons ◽  
Age Groups ◽  
Inward Rectification ◽  
Decay Kinetics ◽  
Glutamatergic Synapses ◽  
Early Postnatal Development ◽  
Paired Pulse ◽  
Age Related ◽  
Hippocampal Ca1 ◽  
Voltage Dependent

We assessed synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) properties during synaptogenesis to describe the development of individual glutamatergic synapses on rat hippocampal CA1 principal neurons. Pharmacologically isolated AMPAR-mediated glutamatergic synaptic currents [evoked by stimulation of the Schaffer Collateral pathway, excitatory postsynaptic currents (EPSCs)], had significantly greater inward-rectification at ages P5–7 compared with P8–18. These inward rectifying EPSCs demonstrated paired-pulse dependent unblocking at positive holding potentials, consistent with voltage-dependent internal polyamine block. Measurements of paired-pulse facilitation did not support altered presynaptic properties associated with inward rectification. Using asynchronous EPSCs (aEPSCs) to analyze populations of individual synapses, we found that quantal amplitudes ( Q) increased across early postnatal development (P5-P18) and were directly modulated by increases in the number of activated receptors. Quantal AMPAR decay kinetics (aEPSC τdecays) exhibited the highest coefficient of variation (CV) from P5 to 7 and became markedly less variable at P8–18. At P5–7, faster quantal kinetics coexisted with much slower kinetics; only slower quantal kinetics were found at P8–18. This supports diverse quantal synaptic properties limited to P5–7. Multivariate cluster analysis of Q, CVτdecay, and median τdecay supported a segregation of neurons into two distinct age groups of P5–7 and P8–18, similar to the age-related segregation suggested by inward rectification. Taken together, these findings support synaptic, calcium permeable AMPARs at a subset of synapses onto CA1 pyramidal neurons exclusively at P5–7. These distinct synapses coexist with those sharing the properties of more mature synapses. These synapses disappear after P7 as activated receptor numbers increase with age.

scholarly journals Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

2022 ◽  
Vol 14 ◽  
Author(s):  
Shuang Chen ◽  
Da Xu ◽  
Liu Fan ◽  
Zhi Fang ◽  
Xiufeng Wang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Receptors ◽  
Neurological Disorders ◽  
Nerve Conduction ◽  
Ionotropic Glutamate Receptors ◽  
Future Studies ◽  
Excitatory Neurotransmission ◽  
The Relationship ◽  
Neuron Injury

Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.

scholarly journals Effect of FMRFamide on voltage-dependent currents in identified centrifugal neurons of the optic lobe of the cuttlefish, Sepia officinalis

2020 ◽  
Author(s):  
Abdesslam Chrachri
Keyword(s):  
Visual Processing ◽  
Calcium Current ◽  
Optic Lobe ◽  
Low Voltage ◽  
Sodium Current ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Outward Currents ◽  
Voltage Dependent ◽  
Inward Currents

AbstractWhole-cell patch-clamp recordings from identified centrifugal neurons of the optic lobe in a slice preparation allowed the characterization of five voltage-dependent currents; two outward and three inward currents. The outward currents were; the 4-aminopyridine-sensitive transient potassium or A-current (IA), the TEA-sensitive sustained current or delayed rectifier (IK). The inward currents were; the tetrodotoxin-sensitive transient current or sodium current (INa). The second is the cobalt- and cadmium-sensitive sustained current which is enhanced by barium and blocked by the dihydropyridine antagonist, nifedipine suggesting that it could be the L-type calcium current (ICaL). Finally, another transient inward current, also carried by calcium, but unlike the L-type, this current is activated at more negative potentials and resembles the low-voltage-activated or T-type calcium current (ICaT) of other preparations.Application of the neuropeptide FMRFamide caused a significant attenuation to the peak amplitude of both sodium and sustained calcium currents without any apparent effect on the transient calcium current. Furthermore, FMRFamide also caused a reduction of both outward currents in these centrifugal neurons. The fact that FMRFamide reduced the magnitude of four of five characterized currents could suggest that this neuropeptide may act as a strong inhibitory agent on these neurons.SummaryFMRFamide modulate the ionic currents in identified centrifugal neurons in the optic lobe of cuttlefish: thus, FMRFamide could play a key role in visual processing of these animals.

Sign in / Sign up

Export Citation Format

Share Document