HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 545/2/333    most recent 2002.031393v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kameyama, M. Search for Related Content PubMed PubMed Citation Articles by Kameyama, M. Related Collections Perspectives

Journal of Physiology (2002), 545.2, p. 333
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.031393

Modulation of inactivation of cardiac L-type Ca²⁺ channels

Masaki Kameyama

Email: kame{at}m.kufm.kagoshima-u.ac.jp

Cardiac pacemaking and contraction are mechanisms intrinsic to the cardiac myocytes. The L-type Ca²⁺ channel is the major voltage-dependent Ca²⁺ channel in cardiac myocytes and plays an important role in pacemaker activity and excitation- contraction coupling. The L-type Ca²⁺ channel has two types of inactivation, i.e. voltage-dependent and Ca²⁺- (ion flux)-dependent inactivation. Voltage-dependent inactivation is thought to involve a mechanical occlusion of the channel pore similar to the 'ball and chain' or 'hinged lid' mechanism described for voltage-dependent K⁺ and Na⁺ channels. Recent studies have revealed that multiple structural elements of pore-forming ₁ subunits, as well as auxiliary subunits, contribute to this inactivation (Hering et al. 2000; Stotz & Zamponi, 2001). Ca²⁺-dependent inactivation involves Ca²⁺ ions passing through the channel or released from intracellular stores such as the sarcoplasmic reticulum (SR). It is suggested that a Ca²⁺-binding EF-hand-like region and/or multiple calmodulin-binding regions in the C-terminus of the _1C subunit (Ca_V1.2) are involved in this type of inactivation (Hering et al. 2000). In most studies, voltage-dependent inactivation of the channel has been investigated with Ba²⁺ as a charge carrier. However, it has been shown that Ba²⁺ also mediates flux-dependent inactivation, although it is not as efficient as Ca²⁺ (Ferreira et al. 1997). Thus, for the precise investigation of the molecular mechanisms of inactivation, it is important to establish a method to appropriately separate the two types of inactivation.

-Adrenergic stimulation increases the whole-cell current through the L-type Ca²⁺ channel 3- to 5-fold. This effect is mostly due to an increased availability of the channels to open. In contrast, the effects of -adrenergic stimulation on inactivation of the channel are not clearly established. Although -adrenergic stimulation has been shown in some studies to slow voltage-dependent inactivation, this effect has not been confirmed in other studies. Ca²⁺-dependent inactivation is usually enhanced by -adrenergic stimulation due to increased Ca²⁺ influx and/or Ca²⁺ release from the SR. Thus, again, it is necessary to separate voltage-dependent inactivation from Ca²⁺ (ion flux)-dependent inactivation.

In two recent studies by Findlay (2002a,b), it was clearly shown that not only Ca²⁺ and Sr²⁺ but also Ba²⁺ can mediate ion flux-dependent inactivation, and that voltage-dependent inactivation can be adequately isolated by using Na⁺ as charge carrier in the presence of tetrodotoxin (a blocker of voltage-dependent Na⁺ channels) and ryanodine (a blocker of Ca²⁺-release channels in the SR). Using this sophisticated method, Findlay confirmed that -adrenergic stimulation slows voltage-dependent inactivation (see also Mitarai et al. 2000).

In two papers in this issue of The Journal of Physiology, Findlay (2002c,d) has extended his previous studies. The Ca²⁺ channel current was recorded in single myocytes as an outward-directed Na⁺ current in the absence of extracellular Ca²⁺ and in the presence of tetrodotoxin and ryanodine. It was found that, under control conditions, the current has fast- and slow-inactivating components as well as a non-inactivating component, with the fast-inactivating component being dominant. A -adrenergic agonist reduces the fast component and increases the non-inactivating component in a dose-dependent manner. These effects are antagonised by the muscarinic agonist carbachol. Based on these and previous studies, the author states that, under physiological conditions, inactivation of the L-type Ca²⁺ channel is dominated by a rapid voltage-dependent process, while under -adrenergic stimulation conditions, voltage-dependent inactivation is replaced by Ca²⁺-dependent inactivation. The studies also reveal a U-shaped voltage dependence of inactivation in the absence of Ca²⁺-dependent inactivation, which is not predicted by a simple Hodgkin-Huxley formalism (cf. Jones, 1999). This suggests that the voltage-dependent inactivation is more complicated than that of K⁺ and Na⁺ channels, although they may share some common basic properties.

At the single-channel level, the gating pattern of the L-type Ca²⁺ channel is characterised by a modal behaviour: in response to repetitive depolarisation, the channel changes the open-close kinetics from one mode to another dramatically. Hess et al. (1984) proposed three modes: mode 0, in which the channel does not open; mode 1, in which the channel opens for a relatively short time (~1 ms); and mode 2, in which the channel opens for a longer time (5-20 ms). In a control state (without -adrenergic stimulation), the channels are mostly in mode 0, moderately in mode 1 and only rarely in mode 2. A -adrenergic agonist produces a more frequent appearance of modes 1 and 2, resulting in the prolongation of the bursting time of openings. This effect may be related to the slowing of inactivation of the whole-cell current seen in the studies of Findlay (2002c,d) and others.

Recent computer models of cardiac action potential incorporate numerous ion channels, pumps and transporters, as well as local concentrations of ions and a number of factors that affect these processes. Such models are widely used for evaluating the contribution of each individual component to cardiac electrical activity under normal and pathophysiological conditions. However, only a few models offer the possibility of modulating the inactivation of the L-type Ca²⁺ channel by -adrenergic and muscarinic stimulation. It will be interesting to see whether the modulation of inactivation shown in Findlay (2002c,d) will reveal new features of Ca²⁺ signalling in cardiac myocytes, both under physiological and pathophysiological conditions.

FERREIRA, G., YI, J., RIOS, E. & SHIROKOV, R. (1997). Journal of General Physiology 109, 449-461.	[Abstract/Full Text]
FINDLAY, I. (2002a). Journal of Physiology 541, 731-740.	[Abstract/Full Text]
FINDLAY, I. (2002b). Journal of Physiology 541, 741-751.	[Abstract/Full Text]
FINDLAY, I. (2002c). Journal of Physiology 545, 375-388.
FINDLAY, I. (2002d). Journal of Physiology 545, 389-397.
HERING, S., BERJUKOW, S., SOKOLOV, S., MARKSTEINER, R., WEI§, R. G., KRAUS, R. & TIMIN, E. N. (2000). Journal of Physiology 528, 237-249.	[Abstract/Full Text]
HESS, P., LANSMAN, J. B. & TSIEN, R. W. (1984). Nature 311, 538-544.	[Medline]
JONES, S. W. (1999). Journal of Physiology 518, 630.	[Abstract/Full Text]
MITARAI, S., KAIBARA, M., YANO, K. & TANIYAMA, K. (2000). American Journal of Physiology - Cell Physiology 279, C603-610.	[Medline]
STOTZ, S. C. & ZAMPONI, G. W. (2001). Trends in Neurosciences 24, 176-181.	[Medline]

This Article Abstract Full Text (PDF) All Versions of this Article: 545/2/333    most recent 2002.031393v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kameyama, M. Search for Related Content PubMed PubMed Citation Articles by Kameyama, M. Related Collections Perspectives