What is slow and fast inactivation of calcium channels?

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dragosb
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What is slow and fast inactivation of calcium channels?

I am a beginner in this field of research and I am not clear waht is it all about this slow and fast inactivation of voltage gated calcium channels.

Please help me

Thank you

littlebush
littlebush's picture
Hi,You know that there are

Hi,You know that there are many type of the voltage gated calcium channels say L ,P/Q ,N and T type .The inactivation refers to their kinetic of the inactivation time,for those have relative long time for inavtivation,we call it slow inactivation ,such as the L type calcium channel ,likewise for those with relatively fast inactivation time,we denote it as fast inactivation for examply,the T type calcium channels.Generally,these parameter are the so-called thinks as gating.They are very complex and also very interesting.If you want to know more ,please consult the book titled ion channels of the excitable membrane by B.Hill.I am sure you can find everything you need in that book.Hope this will help you .

Fraser Moss
Fraser Moss's picture
You have to be careful with

You have to be careful with the use of the words "slow"and "fast" in electrophysiolgy as the terminology is usually applied in relative terms.

In a voltage dependent calcium channel one would describe the inactivation as rapid or fast if at a potential that opens the channel, the current becomes completely inactivated within tens of milliseconds (up to about 50ms). However the timecourse of inactivation will always be voltage dependent and will usually decrease exponentially with membrane depolarization, particularly for T-type calcium channels.

Inactivatoin of L-type channels in contrast will usually take hundreds of milliseconds or seconds. The rate of inactivation of this class of channel is both calcium and voltage dependendent.

Also, just to expand on littlebush's post, here is some background about voltage dependent calcium channel classification.

Functional Characteristics of Voltage Dependent Calcium Channels

Voltage classification

Originally it was assumed that there was only one type of VDCC. However, the first indication that there existed more than one species of VDCC came from recordings of the egg cell membrane of the starfish. The currents could be distinguished by their different voltage thresholds for activation, a result that was also later observed in multiple cell types from different organisms. On the basis of channel biophysics, VDCC currents were individually classified according to:

1) The magnitude of the depolarisation step required to activate the channel.
2) The time-course of inactivation of the channel following its activation.
3) The magnitude of the single channel conductance, which is unique to each channel subtype.

The first of these parameters categorises VDCC into two broad groups according to their voltage dependence of activation. Low voltage activated (LVA) or T-type (transient) channels activate at potentials slightly above the resting potential, gate fast, rapidly inactivating transient currents with a typical single channel conductance of ~8pS, exhibit Ca2+ currents of equal or greater magnitude than Ba2+ currents and are typically more sensitive to block by Ni2+ than Cd2+. These properties suggested that these channels were involved in the pacemaker activity in cardiac myocytes and neurones.

The high voltage activated (HVA) channels have a threshold for activation substantially above the resting potential (towards 0mV), larger single channel conductances than T-type (Figure 1.2), display larger Ba2+ than Ca2+ conductances, are highly sensitive toCd2+ block and inactivate more slowly. Early biophysical analysis identified two distinct components of HVA current. The L-type was so called because of its long-lasting, slowly inactivating current and possessed a single channel conductance of approximately 25pS. Another property peculiar to the L-type current is that it is both voltage and calcium dependently inactivated. The functional importance of calcium-induced inactivation is that it provides a negative feedback mechanism that limits calcium entry in to the cell.

The biophysical properties of N-type current make it very difficult to identify from other current types. Named N-type because its intermediate nature was neither L- or T- type, it displayed an average single channel conductance of 13pS (later modified to ~18pS), activation over a range of potentials between those of T- and L- type channels, and inactivation over an extremely broad range (-80 to -20 mV). These multiple degrees of inactivation, broad activation ranges and the propensity to remain available for activation at relatively positive holding potentials could be explained by different gating modes, the expression of different channel splice-variants, or differential association with an auxiliary subunit.

Application of organic reagents and peptide toxins developed a pharmacological basis for VDCC current classification. These studies clarified the ambiguity surrounding the nature of N-type current, and identified additional current types according to their sensitivity to selective pharmacological agents.

Pharmacological classification

T-type

T-type currents can be clearly identified by their biophysical properties alone, which is fortunate for researchers since a pharmacologically selective compound was only recently discovered. The application of Ni2+ or amiloride has often been used to reduce T-type currents, however neither the cation nor drug have ever proven particularly selective. It was proposed that a novel Ca2+ channel antagonist, mibefradil, could selectively block T-type current. However this compound has been shown to block HVA VDCC types, and displays an especially high-affinity binding for VDCCs when in the inactivated state. Kurtoxin, isolated from the venom of the South African scorpion Parabuthus transvaalicus, is potentially the first truly selective T-type antagonist. This peptide demonstrates over 600-fold selectivity for block of LVA current over HVA currents and works by modifying the channel gating properties, as demonstrated by shifting the voltage dependence of activation of cloned T-type channels to more depolarised voltages rather than blocking the channel pore. Nevertheless, kurtoxin also causes pronounced slowing of rat brain type IIA Na+ channel current activation and inactivation, indicating that although it is selective for a particular VDCC current, it is not exclusively a Ca2+channel antagonist and that T-type VDCCs and voltage-dependent Na+ channels probably, both of which control membrane excitability, share a common toxin-binding motif.

L-type

The L-type current is sensitive to modulation by the organic reagents called dihydropyrines (DHPs) whereas the LVA T-type channels are not. Nitrendipine, and nifedipine have both been shown to be L-type antagonists whilst (-)BayK8644, another dihydropyridine enhances L-type current. However, it has become apparent that the DHP agonists and antagonists also act upon other VDCC currents, albeit with less potency. In addition to the DHPs L-type current is modulated by phenylalkyamines (PAA e.g. verapamil) and benzothiazepines (BTZ e.g. diltiazem), which act at allosterically linked receptor sites to block Ca2+current. L-type channels are probably the primary sites of action for BTZs and PAAs, but these compounds are also non-selective, inhibiting Ca2+ currents from other channel types.

N-type

N-type current is insensitive to DHP modulation but is instead blocked by toxins extracted from the venom of the fish-hunting snail Conus geographus. In mammalian neurones, the toxin fraction ω-conotoxin GVIA (ω-ctx GVIA) is a highly selective and irreversible blocker of only N-type VDCCs. The sensitivity of VDCC current to this particular toxin is now the standard defining criterion of N-type current. A second toxin fraction from the venom of the Conus magnus snail, ω-conotoxin MVIIA (ω-ctx MVIIA) blocks N-type current with similar potency and efficiency as ω-ctx GVIA, but binds reversibly. The synthetic version of this toxin (SNX-111) has entered clinical trials for the control of pain and as a neuroprotective reagent

.
P/Q-type

The predominant VDCC current in cerebellar Purkinje cell bodies (>80%) was designated the P-type. It could be separated from L- and N-type currents because it was insensitive to block by DHPs or ω-ctx GVIA, but was specifically blocked by the polyamine-containing fraction of funnel web spider toxin venom, FTX. Subsequent investigations used a more refined peptide venom fraction ω-Agatoxin IVA (ω-AgaIVA), which proved to be a more potent and selective P-type inhibitor (IC50 ~2 nM). P-type current is slow to inactivate during prolonged depolarisations and exhibits multiple conductance levels of 9, 14, and 19 pS (in 110 mM Ba2+), which could be attributable to molecular channel diversity or differential subunit associations.
A similar current identified in rat cerebellar granule cells was called Q-type. Like P-type current, Q-type is HVA, DHP and ω-ctx GVIA insensitive, and potently inhibited by the ω-conotoxin MVIIC. It can however be pharmacologically distinguished from P-type by its lower sensitivity to ω-AgaIVA (IC50 ~200mM). It also displays an inactivating waveform even in the presence of Ba2+. Despite these differences, the similarity between P- and Q- type currents has often led to the two classes being grouped into a single P/Q-class. However, recent identification of some of the molecular determinants for P- and Q-type current has allowed researchers to be less ambiguous in their current classification.

R-type

If L-, N-, P-, and Q- currents comprised the total VDCC current in a neurone, application of a cocktail of DHPs, ω-ctx GVIA and ω-AgaIVA, each at a sufficient but non-toxic concentration, would completely abolish all Ca2+ current stimulated by a prolonged depolarisation (this would eliminate the T-type component). This does not occur in the majority of neurones due to the presence of a resistant R-type current. First classified as another component of cerebellar granule cell current, much controversy surrounds the R-type channels and their molecular components. Their threshold for activation is usually at potentials between those for LVA or HVA channels, they inactivate rapidly like T-type channels and are more sensitive to block by Ni2+ than Cd2+.

This is all pretty old school stuff now and the channels are also classified by their molecular componenets; especially the alpha subunit which forms the pore.

Broadly

L-type α1 subunit genes (CaV1.x)

α1S = CaV1.1
α1C = CaV1.2
α1D = CaV1.3
α1F = CaV1.4

DHP-insensitive neuronal α1 subunit genes (CaV2.x)

α1A = CaV2.1 - P/Q-type
α1B = CaV2.2 - N- type
α1E = CaV2.3 - R-type

Low voltage activated T-type α1 subunits (CaV3.x)

α1G = CaV3.1
α1H = CaV3.2
α1I = CaV3.3

Fraser Moss
Fraser Moss's picture
Here's a nice paper about T
dragosb
dragosb's picture
Thank you for the

Thank you for the informations. I was in a little bit of trouble because of the following article where there was a tau fast and tau slow described for the inactivation of Cav1.2 and Cav1.3 channels.

I thought that in that case they refer to fast inactivation caused by calcium and slow inactivation that is voltage dependent.

Please tell me if it is the case or not?

Thanks again

Article:
0031-6997/05/5704-411-425$7.00
Pharmacol Rev 57:411-425, 2005
IUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels
William A. Catterall, Edward Perez-Reyes, Terrance P. Snutch and Joerg Striessnig

Fraser Moss
Fraser Moss's picture
I think you're reading too

I think you're reading too much into that.

The Cav1 family of channels (except Cav1.4) all inactivate in a manner that can be fitted best with a 2 component exponential which has a slow and a fast component expressed as Tau slow and tau fast. These merely refelect two subconductance states as the channels inactivate and both taus contain components of calcium mediated and voltage mediated inactivation. The Cav2 family inactivate with two components too and they are not calcium dependent.

I found an interesting article in press that decribes how Cav1.4 avoids the calcium dependent inactivation.

http://www.pnas.org/cgi/reprint/0604621103

hyunjoe
hyunjoe's picture
Quote:

Quote:

The Cav1 family of channels (except Cav1.4) all inactivate in a manner that can be fitted best with a 2 component exponential which has a slow and a fast component expressed as Tau slow and tau fast. These merely refelect two subconductance states as the channels inactivate and both taus contain components of calcium mediated and voltage mediated inactivation. The Cav2 family inactivate with two components too and they are not calcium dependent.

This is right, all the messages before were not useful to define what was "slow and fast" inactivation. These terms refer to the exponential taus as frasermoss as told in his las post. The other information are very useful but not for the question you have asked. But, don't think slow and fast inactivation is reserved to HVA channels, T-type inactivation have also been characterized with 2 or 3 exponential taus.