Regulation of Ion Channels in Myocardial Cells and Protection of Ischemic Myocardium

Introduction The slow (L-type) Ca2 (CaL) channels of myocardial cells are physiologically regulated by a number of mechanisms, including (a) phosphorylation by various protein kinases (PKs), (b) pH, (c) ATP, and (d) Ca2 ions [93,105,112]. They are also regulated by the alpha subunit of the Gs coupling protein [148]. This regulation of the slow Ca2 channels is enabled by their special properties, and allows their control by factors intrinsic and extrinsic to the cell. Myocardial cells must closely control the concentration of intracellular Ca2 (Cai), and one mechanism for such control is the regulation of the activity of the slow Ca2 channels and hence of Ca2 in ux into the cell. Under pathophysiological conditions, for example during regional ischemia, the activity of the slow Ca2 channel is depressed, and this serves as one protection mechanism for the heart [108,112]. In addition, the force of contraction of the heart, which is varied in accordance with the physiological needs of the body, is controlled by the amount of Ca2 in ux into the ventricular myocardial cell, which, in turn, is modulated by the sympathetic and parasympathetic innervation and by circulating hormones and autacoids. The ATP-sensitive K (KATP) channels also help to indirectly control the Ca2 in ux into the myocardial cells, and when activated during ischemia, they serve as a second protection mechanism. This review-type article will summarize the major mechanisms for the regulation of the slow Ca2 channels of myocardial cells that have been reported, with emphasis on research carried out on chick and rat in the authors' laboratory. For additional speci®c references on related work from other laboratories, the reader is referred to several review-type articles given in the bibliography. This review article is an updated, expanded, and rearranged version of [116]. In addition, how these CaL channels and KATP channels serve to protect myocardial cells during ischemia will be discussed. Types of Ca2 Channels Five different types of voltage-dependent Ca2 channels have been described for nerve and muscle cells (Table 1) [116]. Two of them are known as: L-type (or long-lasting or kinetically slow) and T-type (or transient or kinetically fast). Muscle ®bers possess primarily the L-type and Ttype, with the T-type channels being very sparse or absent in some types of adult muscles. That is, in adult cardiac muscle cells, the major inward Ca2 current is through the L-type slow Ca2 channels. The major differences between the slow (L-type) Ca2 channels and the fast (Ttype) Ca2 channels are summarized in Table 2 [115]. The kinetics of activation and inactivation are slower for the L-type; i.e. the slow ICa L turns on (activates) more slowly and turns off (inactivates) more slowly. In addition, the voltage ranges over which these channels operate are different, the threshold potential and inactivation potential being higher (more positive) for the slow Ca2 channels. Therefore, the L-type channels are high threshold (activation voltage of y45 to y35 mV), whereas the T-type channels are low threshold (activation voltage of y60 to y50 mV). The single-channel conductance is greater for the slow Ca2 channel: 18±26 pS (L-type) versus 8± 12 pS (T-type) (Table 1). The slow Ca2 channels are regulated by cyclic nucleotides and phosphorylation. whereas the fast Ca2 channels are not. Finally, the slow Ca2 channels are blocked by Ca2 antagonist drugs and opened by Ca2 agonist drugs, whereas the fast Ca2 channels are not affected (Table 2). In some respects, the fast Ca2 channels behave like fast Na channels, except that they are Ca2 selective (rather than Na selective) and are not blocked by tetrodotoxin (TTX). A number of changes in the slow Ca2 channels occur during development and aging. These