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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Ca2+ Signaling

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The process of calcium signaling comprises a series of molecular and biophysical events that link an external stimulus to the expression of some appropriate intracellular response through an increase in cytoplasmic Ca2+ as a signal. The external signal is most commonly a neurotransmitter, hormone or growth factor; but in the case of excitable cells, the initial chemical stimulus may bring about membrane excitation, which in turn activates a calcium-signaling pathway.

Release of intracellular Ca2+ is mediated primarily via inositol 1,4,5-trisphosphate receptors and ryanodine receptors

The calcium ions that give rise to a [Ca2+]i signal can come from one or two sources: intracellular Ca2+ stores and external Ca2+ entering across the plasma membrane. Typically, both sources are utilized. The most ubiquitous of the intracellular Ca2+ release mechanisms involves the phosphoinositide specific phospholipase C (PI-PLC)-derived second messenger IP3, which acts by binding to a specific receptor on the endoplasmic reticulum or to a specialized component of the endoplasmic reticulum. The functional IP3 receptor/channel appears to be a homotetramer containing four binding sites for IP3. Distinct subtypes of the receptor exist, representing products of at least three distinct genes, and additional forms arise as a result of alternative splicing of mRNA. The origin of IP3 and the characteristics of IP3 receptors are discussed in Chapter 21.

The interaction of IP3 with its receptor involves complex and poorly understood regulatory interactions among the receptor, IP3 and Ca2+, the latter exerting influence from both the cytoplasmic and luminal aspects of the receptor. Ca2+ in the lumen of the ER appears to sensitize the receptor to IP3. On the cytoplasmic surface, low concentrations of Ca2+ sensitize the receptor while higher concentrations are inhibitory. These actions may contribute to the “all-or-none” oscillatory behavior of [Ca2+]i signals seen in some cell types. This phenomenon will be discussed in more detail below.

The other major type of intracellular Ca2+-mobilizing receptor is the ryanodine receptor. The ryanodine receptor is named for a toxin that binds to the molecule with high affinity and which led to its purification and characterization. It is also a homotetramer, and the IP3 and ryanodine receptors share considerable structural homology [5]. In its most specialized setting, in skeletal muscle, the ryanodine receptor is gated by a direct conformational interaction with a dihydropyridine receptor in the t-tubule membrane (see Chap. 43). This coupling allows for rapid release of stored Ca2+ when an action potential invades the t-tubule system. However, the physiological ligand for the ryanodine receptor is usually Ca2+ itself; that is, it is considered to be a Calcium-Induced Calcium Release (CICR) receptor—Ca2+ channel. Because Ca2+ can sensitize the IP3 receptor to IP3, the IP3 receptor also can exhibit CICR behavior. However, some IP3 is always required for its action, while the ryanodine receptor can function as a “pure” CICR receptor. Although the ryanodine receptor is thought to be regulated primarily by CICR, there is also a small water-soluble molecule that can function as a regulatory ligand for at least some forms of the ryanodine receptor. Cyclic adenosine diphosphate ribose (cADPr) [6] functions in a manner somewhat similar to IP3: it increases the probability of the ryanodine receptor channel opening by increasing its sensitivity to Ca2+. It is tempting to speculate that Ca2+ signaling in neurons may be regulated by changing concentrations of cADPr, and there is limited evidence for this suggestion. In at least one cell type, the sea urchin oocyte, both the IP3 receptor and a cADPr-sensitive ryanodine receptor seem to function in a somewhat redundant, or perhaps cooperative, manner to produce a regenerative intracellular Ca2+ signal.

Ca2+ enters cells either via voltage- or ligand-dependent channels or by means of capacitative entry

There are at least three fundamental mechanisms of regulated calcium ion entry across the plasma membrane. These involve the actions of voltage-dependent Ca2+ channels, ligand-gated channels and the process of capacitative calcium ion entry.

Voltage-dependent Ca2+channels are found in a variety of excitable cell types, including neurons, muscles and endocrine and neuroendocrine cells [2]. They are almost never found in classical “nonexcitable” cells, such as epithelial cells, leukocytes and fibroblasts. By definition, these channels can be activated by membrane depolarization and are subject to the complex combinations of voltage-dependent activation and voltage-dependent or calcium-mediated inactivation mechanisms similar to the voltage-dependent regulation of Na+ channels described by Hodgkin and Huxley (see Chap. 6). These are the Ca2+ channels that provide activator Ca2+ for cardiac contractility, for contraction of some smooth muscle types and, generally, for discharge of neurotransmitters. In most instances, their activation is initiated by membrane depolarization, whether by a propagated action potential or by the opening of other ligand-gated channels. In some cases, the channels are activated by removing an inhibitory influence, such as a decrease in a hyperpolarizing K+ conductance, or by sensitizing the channels to activation at resting membrane potential through phosphorylation.

There are at least five different molecular types of voltage-dependent Ca2+ channel, differing in their gating kinetics, modes of inactivation and regulation by Ca2+ and sensitivity to specific marine toxins [7] (see Box 23-1). The distinctions between the types of channel are of considerable interest because the different subtypes are believed to subserve different cellular functions. For example, the control of neurotransmitter release in peripheral sympathetic neurons appears to be under the predominant control of N-type calcium channels.

Box Icon

Box 23-1

Voltage-Gated Calcium Ion Channels.

Ligand-gated ion channels are numerous, and some permit sufficient entry of Ca2+ to provide for cellular activation. Here, receptor-gated channels denote channels that are gated directly by binding of agonist, not through the generation of second messengers, generally because the ligand-binding site is located on the channel protein. These are invariably nonspecific cation channels; there are as yet no clearly identified receptor-gated channels that are specific for Ca2+ ions. These channels are discussed in detail in other chapters in this volume (see Chaps. 10, 11, 13, 15–17).

Capacitative Ca2+ entry is by far the predominant mode of regulated Ca2+ entry in nonexcitable cells, but it also occurs in a number of excitable cell types. This is the pathway of Ca2+ entry usually associated with the activation of PLC and the formation of IP3 (see Chap. 21). Intracellular application of IP3 mimics the ability of hormones and neurotransmitters to activate calcium ion entry, and activation of calcium ion entry by hormones and neurotransmitters can be blocked by intracellular application of low-molecular-weight heparin, a potent antagonist of IP3 binding to its receptor. There is considerable evidence for the presence of an IP3 receptor, or a protein similar to it, in the plasma membrane of some cell types. I(1,3,4,5)P4, a product of IP3 phosphorylation, has been shown in some cases to augment the action of IP3 in activating calcium ion entry, but in others, IP3 alone is clearly sufficient.

However, the current view of the regulation of calcium ion entry by PLC-linked stimuli holds that activation occurs not as a direct result of the action of IP3 on the plasma membrane but, rather, as a result of the depletion of calcium ions from an intracellular store by IP3 [8]. In the context of this capacitative model, the actions of intracellularly applied IP3 and heparin reflect the effects of these maneuvers on the intracellular release process, rather than directly on the plasma membrane. The reported actions of I(1,3,4,5)P4, if in fact they do represent physiological control mechanisms, may reflect its ability of I(1,3,4,5)P4 to augment the calcium-releasing ability of IP3, rather than a distinct and specific action at the plasma membrane. The capacitative model for calcium ion entry originally was proposed on the basis of circumstantial evidence from the relative rates of emptying and refilling of intracellular stores of calcium, but more direct tests of the model have arisen from the discovery of reagents, such as thapsigargin and cyclopiazonic acid, that inhibit the Ca2+-ATPase responsible for storing intracellular calcium in the IP3-sensitive pool (Fig. 23-3). These reagents make it possible to deplete this pool of its Ca2+ without stimulating the formation of any inositol phosphates. Thus, numerous reports have demonstrated that in cells treated with such agents, Ca2+ entry across the plasma membrane is activated [9]. Importantly, this Ca2+ entry is not facilitated by concomitant stimulation of inositol phosphate production.

Figure 23-3. Structures of compounds that inhibit sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) calcium pumps.

Figure 23-3

Structures of compounds that inhibit sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) calcium pumps.

Two general mechanisms by which a depleted intracellular Ca2+ pool might communicate with the plasma membrane have been considered [3]. There is evidence from a number of studies that the IP3 receptor is associated with the cytoskeleton, and this association might result in tethering of the IP3 receptor to the plasma membrane. Depletion of intracellular calcium stores causes a conformational change in the IP3 receptor, which could be conveyed to the plasma membrane via the cytoskeleton or by a more direct protein—protein interaction. Alternatively, signaling could occur through the action of a diffusible messenger released by the depleted intracellular calcium store and acting on calcium channels in the plasma membrane. Proposed candidates for this signaling messenger are cGMP (Chap. 22), a metabolite of cytochrome P450, and the poorly characterized calcium influx factor (CIF) (reviewed in [3,9]). However, subsequent studies have cast doubt on each of these proposals. There is pharmacological evidence that a GTP-dependent step is involved as well as a tyrosine kinase (see Chaps. 20 and 25). These latter findings have led to the proposal that vesicle transport may be involved, in that preformed and active calcium channels may be inserted into the membrane by vesicle fusion. There is little direct evidence for this suggestion, however.

In contrast to the case for voltage-dependent and receptor-gated channels, the channels associated with capacitative calcium ion entry only recently have been characterized electrophysiologically. In leukocytes, the current associated with the depletion of intracellular Ca2+ stores is highly Ca2+-selective, even over Ba2+, in contrast to other known Ca2+ channels, and, on the basis of noise analysis, is believed to involve minute single channels [10] (see Chap. 6). This is the calcium release-activated calcium current (ICRAC). However, in other cell types, the current is more akin to “conventional” Ca2+ channels in being similarly permeable to Ca2+ and Ba2+ and showing readily identifiable single channels with conductances in the picosiemens range. These marked electrophysiological distinctions may be indicative of distinct channel types mediating capacitative calcium ion entry in different cell types.

While the molecular identity of the capacitative Ca2+ entry channel is not known, a candidate is a homolog of the Drosophila mutant trp. This photoreceptor mutant is incapable of maintaining a sustained photoreceptor potential. This phenotype is mimicked by the calcium ion entry blocker lanthanum, suggesting that the deficit is related to a failure of calcium ion entry. The photoreceptor signaling mechanism in insects involves an IP3-signaling system, and it may be that the normally sustained photoreceptor potential depends on capacitative calcium ion entry [11]. When trp was cloned and sequenced, homology was detected between this protein and the α1 subunit of the voltage-sensitive calcium channel, also termed the dihydropyridine receptor, which is believed to contain the ion channel region of the protein. As might be expected, trp does not contain the charged residues in the S4 transmembrane segment which are believed to provide the voltage-sensing capabilities of the voltage-sensitive channel. Six distinct mammalian homologs of Drosphila trp have been cloned at least partially from human material and designated Htrp-1 through -6 [12]. Some of these proteins have been expressed in mammalian cells and have been shown to augment capacitative calcium ion entry.

The major function of capacitative calcium ion entry is to provide for sustained Ca2+ signaling. However, it is also important in providing a means for rapid replenishment of intracellular stores following their release by IP3 and the cessation of agonist activation. How is this accomplished in those excitable cells which do not express capacitative calcium ion entry? The answer may be that excitable cells generally do, while nonexcitable cells generally do not, express a rapidly turning over sodium—calcium exchange transporter. This transporter could provide an energy-efficient route for rapidly adjusting cytoplasmic Ca2+ in response to rapid uptake demands of a depleted intracellular Ca2+ store. Because the resting turnover of this exchanger is relatively fast, it may be that such a pathway replenishes intracellular stores in the absence of any store-dependent regulation.

Periodic temporal and spatial patterns of Ca2+ signaling give rise to calcium oscillations and waves

As discussed above, the IP3 receptor is subject to complex and only partially understood regulation by both IP3 and calcium. The complicated kinetic behavior of the IP3 receptor is believed to underlie calcium oscillations and waves. In excitable cells, oscillations in [Ca2+]i which reflect periodic fluctuations in membrane electrical activity have been known for some time, the clearest example being the rhythmic cardiac action potentials that drive bursts of Ca2+ release, entry and extrusion and thereby maintain the pumping activity of the heart. However, [Ca2+]i often will oscillate in nonexcitable cells or in excitable cells through mechanisms which have nothing to do with the excitable nature of the surface membrane. Much effort has been devoted to understanding the control mechanisms giving rise to [Ca2+]i waves and oscillations [13].

Intracellular calcium oscillations generally fall into one of two categories involving different mechanisms. The two major kinds of [Ca2+]i oscillation are baseline transients, or spikes, and sinusoidal oscillations. Figure 23-4 illustrates these two oscillatory patterns. Baseline spikes are characterized by rapidly-rising transient increases in [Ca2+]i rising from a baseline of [Ca2+]i which is generally quite close to the resting concentration. In contrast, sinusoidal oscillations more closely resemble true sine-wave oscillations; they are generally of a higher frequency than baseline spikes, >1/min as opposed to frequencies of <1/min for baseline spikes. They also generally appear as symmetrical oscillations superimposed on a sustained concentration of [Ca2+]i somewhat above the prestimulus baseline. Another notable difference between the two types of oscillation is that baseline spikes may, at least in some instances, continue throughout prolonged periods of stimulation, while sinusoidal oscillations tend to diminish with time, generally lasting for only a few minutes. However, the most significant and characteristic distinction between the two types of oscillation is the relationship of the oscillation amplitude and frequency to stimulus strength, or agonist concentration. For baseline spikes, increasing the agonist concentration increases the frequency with little effect on the amplitude, while for sinusoidal oscillations, increasing the agonist concentration increases the average [Ca2+]i without affecting the frequency of the oscillations. Furthermore, for baseline spikes, but not for sinusoidal oscillations, the latency before the first [Ca2+]i spike is inversely related to the agonist concentration. The same mechanism underlying the varying frequency of spiking also may be responsible for the varying latency for the first spike, but this is not necessarily so. The persistent, constant amplitude baseline spikes require a positive feedback mechanism, sometimes called feed-forward, to generate the spikes, with either a negative feedback or some capacity limitation, such as full depletion of an intracellular pool, to terminate each spike. However, negative feedback alone is sufficient to explain the behavior of constant-frequency sinusoidal oscillations.

Figure 23-4. Patterns and mechanisms for major types of [Ca2+]i oscillation.

Figure 23-4

Patterns and mechanisms for major types of [Ca2+]i oscillation. A, Left: A single rat hepatocyte treated with vasopressin exhibits low-frequency baseline spikes of [Ca2+]i. A, Right: The mechanism for baseline [Ca2+]i spiking is seen as being initiated (more...)

In most instances, baseline spiking will continue for at least a few cycles in the absence of extracellular Ca2+, and thus, it is generally agreed that they represent cycles of discharge and reuptake of Ca2+ by intracellular stores. Although other models have been proposed, the currently favored mechanism of baseline [Ca2+]i spiking involves fluctuations in [Ca2+]i while cellular concentrations of IP3 are constant (Fig. 23-4). Models along this theme require that Ca2+ itself provide both positive and negative regulation of the [Ca2+]i signal. An important piece of evidence for such regulation would be the demonstration of [Ca2+]i spiking induced by direct intracellular application of IP3. This has been demonstrated in oocytes and, in a few cases, in small, mammalian cells by intracellular introduction of IP3 through whole-cell patch pipette perfusion. These findings suggest a mechanism that operates distally to the production of IP3 exists for generating [Ca2+]i spikes.

As discussed above, biphasic regulation of IP3-induced Ca2+ release by Ca2+ is reminiscent of the behavior of the CICR channel from skeletal muscle. In addition, the inhibitory action of Ca2+ on IP3-induced Ca2+ release develops more slowly than the activation, with a time constant of about 0.5 sec. There is obvious similarity between this scheme, which involves a rapid Ca2+ activation of release followed by a more slowly developing Ca2+ inhibition, and the feed-forward and feedback regulation of action potentials by depolarization. As discussed above, changes in ER luminal [Ca2+] also may regulate the sensitivity of the IP3 receptor. Thus, these kinetically distinct modes of regulation of the IP3 receptor by both cytoplasmic and luminal Ca2+ may provide the ingredients for production of regenerative spikes and waves of [Ca2+]i.

Much less attention has been paid to sinusoidal oscillations of intracellular Ca2+, although strictly speaking, they may represent the only instance in which the term “oscillations” is applied correctly. These are roughly symmetrical fluctuations usually superimposed on a raised basal level of [Ca2+]i. The most significant characteristic of these oscillations is their constant frequency at different agonist concentrations. These sinusoidal oscillations are considerably simpler than the baseline spike type of [Ca2+]i oscillation and can be explained most simply by a single negative feedback on the [Ca2+]i-signaling mechanism. Although this may not apply in all cases, it appears that the negative feedback responsible for the sinusoidal oscillations is often due to protein kinase C (PKC). The site of negative inhibition appears to be on or proximal to PI-PLC. Activation of PI-PLC increases diacylglycerol (DAG), which in turn activates PKC. The latter feeds back and inhibits PI-PLC (see Chap. 21). This leads to a diminution in DAG production, diminished PKC activity and relief of the inhibition of PI-PLC. Continuous cycling of this delayed feedback loop generates oscillations in PI-PLC activity, which, in the absence of some feed-forward input, gradually damp down to a sustained level under tonic control by the opposing forces of receptor activation and PKC inhibition. It is important to point out that in this particular scheme [Ca2+]i is simply a passive follower of the oscillating IP3 production and plays no obvious active role in generating or modulating the oscillations. Thus, this particular type might more appropriately be called “DAG oscillations” or “PI-PLC/PKC oscillations” (Fig. 23-4).

Release of intracellular Ca2+ may occur from “calciosomes,” a subfraction of the endoplasmic reticulum

There is considerable evidence placing the major site of calcium sequestration and the source of intracellular calcium for signaling in the ER. In addition to the points already made, early subcellular fractionation studies reported good correlations between classical enzymatic markers for ER and ATP-dependent Ca2+ accumulation, or IP3-mediated Ca2+ release. Calcium uptake into the IP3-sensitive store is augmented by oxalate, a property generally associated with the ER.

However, there are some inconsistencies with the idea that the IP3-sensitive calcium store and the ER are entirely coincident. For one, there is really no correlation between the quantity of ER present in a given cell type and its sensitivity to calcium signaling through IP3. In contrast to the studies cited above, there are at least an equal number of subcellular fractionation studies in which a separation of IP3-induced Ca2+ release or IP3 binding from enzymatic markers for the ER has been observed. Perhaps the sarcoplasmic reticulum of muscle presents the best characterized paradigm for an organelle distinct from generic ER and specialized for storing and releasing calcium (see Chap. 43). A biochemical characteristic of sarcoplasmic reticulum that distinguishes it from ER is the presence of high concentrations of a high-capacity, low-affinity calcium-binding protein, calsequestrin. A similar protein is found in nonmuscle cells, calreticulin, a protein structurally and functionally homologous to calsequestrin. On the basis of such findings, it was proposed that an organelle specialized for storing and releasing calcium existed and that this organelle was distinct from generic ER. It has been proposed that this organelle be designated “calciosome” [14].

With the exception of skeletal muscle, perhaps the most extensively characterized cell with respect to its Ca2+-releasing and -sequestering organelles is the Purkinje cell of the cerebellum. The Purkinje cells of birds are especially amenable to immunocytochemical studies because they contain much higher concentrations of IP3 receptors than any other cell type and unusually high concentrations of SERCA pumps and ryanodine receptors. In addition, the major calcium-storage protein is almost identical to mammalian calsequestrin, which facilitates immunocytochemistry because of the availability of high-affinity antibodies. In these cells, IP3 receptors are not linked tightly to SERCA pumps or even calsequestrin. However, a population of vacuoles that were positive for calsequestrin as well as for either the IP3 receptor or the ryanodine receptor was found. This could qualify these structures as calciosomes since presumably they are involved in storing as well as releasing calcium [15]. Specialized stacks of ER, rich in IP3 receptor but without substantial quantities of SERCA pumps or calsequestrin, were suggested to act as either reservoirs of receptor or buffers of cytoplasmic IP3. Interestingly, overexpression of IP3 receptors in fibroblasts leads to the formation of structures similar to the IP3 receptor-containing ER stacks of Purkinje cells.

Although the nature of the calciosome as a specialized subcompartment of the ER is widely accepted [15], the term “calciosome” has not gained universal acceptance. This may be due to the fact that in many systems the distinction between the calciosome and the ER is still not established clearly [16].

Although distinct, Ca2+-signaling events in excitable and nonexcitable cells share some common characteristics

Traditionally, calcium-signaling research has been divided into two separate categories: studies focusing on excitable cells, like nerve and muscle, and studies focusing on electrically nonexcitable cells, such as epithelial or blood cells. Although both electrically excitable and nonexcitable cells utilize the release of intracellular Ca2+ as one means of generating cytoplasmic calcium signals, excitable cells often accomplish this by CICR while for nonexcitable cells the predominant mechanism involves IP3 [17]. Also, signaling in both cell types depends to a large degree on plasma membrane Ca2+ channels; but the Ca2+ channels in the plasma membranes of nonexcitable cells do not appear to be regulated by membrane potential, and their pharmacology is quite distinct from that of the channels in excitable cells. However, calcium-signaling mechanisms in excitable and nonexcitable cells may be much more alike than is generally appreciated. A general paradigm for Ca2+ signaling in virtually all cell types has evolved. This paradigm involves a coordinated regulation of intracellular calcium ion release and calcium ion entry across the plasma membrane of the cell [17]. For reasons probably having to do with the distinct functions subserved by excitable and nonexcitable cells, interesting distinctions as well as similarities in basic mechanisms have evolved in these two general cell types.

In electrically nonexcitable cells, Ca2+ signaling is typically a biphasic process. Neurotransmitters and hormones cause a release of calcium ions to the cytoplasm from an intracellular organelle, and this is followed by entry of calcium ions into the cytoplasm across the plasma membrane. The intracellular-release phase of the calcium signal is attributable to IP3, while the second phase of the response is attributed to capacitative calcium ion entry, a process of retrograde signaling such that the empty calcium-storage organelle produces a signal for calcium ion entry across the plasma membrane.

In many instances, neurons and other electrically excitable cells also may utilize the IP3-signaling system. For example, there are smooth muscle types which function in the IP3 mode, the voltage-dependent calcium channel and CICR mode or even combinations of the two. In some instances, when intracellular calcium ions are released by IP3 in excitable cells, this may be coupled to capacitative calcium ion entry, but there are clear examples where this is not the case. Rather, virtually all excitable cells have plasma membrane Ca2+ channels that are activated by membrane depolarization. In addition, excitable cells frequently express another intracellular Ca2+ release channel, the ryanodine receptor (discussed above). The physiological activator of the ryanodine receptor is believed to be Ca2+ itself; the channel opens when the Ca2+ concentration in its vicinity increases rapidly, generating CICR, and this can give rise to the regenerative “all-or-none” calcium ion release behavior for which muscle and nerve cells are noted. In heart cells, for example, Ca2+ signaling is initiated by membrane depolarization, which activates surface membrane voltage-gated Ca2+ channels. A rapid entry of calcium ions serves as a “trigger” for activating the ryanodine receptor and, subsequently, a much larger release of intracellular calcium ions [17].

The common conceptual feature of these two calcium-signaling motifs (Fig. 23-5) is that they provide tight coordination of calcium ion entry and intracellular calcium ion release. They also provide amplification for the calcium signal but in functionally distinct ways. In excitable cells, the process of CICR amplifies the magnitude and spatial distribution of the momentary calcium signal, assuring, in the case of the heart for example, sufficient Ca2+ for catalyzing rapid cross-bridge formation and force development. In nonexcitable cells, the retrograde signaling provided by capacitative calcium ion entry amplifies the duration of the calcium signal, providing sustained, tonic responses of, for example, exocrine gland cells.

Figure 23-5. Motifs of [Ca2+]i signaling.

Figure 23-5

Motifs of [Ca2+]i signaling. In electrically excitable cells (left), Ca2+ may enter when voltage-dependent Ca2+ channels are activated by the depolarization associated with action potentials. This Ca2+ can cause further release of intracellularly stored (more...)

These characteristics of excitable and nonexcitable cells are not as distinct as once believed. For example, capacitative calcium ion entry contributes to calcium signaling in a number of excitable cell types [9]. Also, as discussed in the preceding section, the all-or-none regenerative calcium signals which occur in nerves and muscles now are known to occur in nonexcitable cells. Thus, it is interesting that while the term nonexcitable appropriately describes the electrophysiological behavior of their surface membranes, the regenerative intracellular Ca2+ spikes that often are exhibited by so-called nonexcitable cells constitute a clear example of excitable behavior of their intracellular milieu. This occurs because the IP3 receptor functions as a CICR receptor whose sensitivity to Ca2+ is regulated by the binding of IP3 and vice versa. Perhaps this is not so surprising given the considerable homology between the amino acid sequences of the IP3 and ryanodine receptors. Electrically nonexcitable cells generally contain only a single, rather homogeneous intracellular pool of calcium, which is sensitive to IP3, while electrically excitable cells may have a more complex arrangement of intracellular calcium pools regulated by distinct mechanisms.

Thus, there may be substantially greater similarity between Ca2+-signaling systems in excitable and nonexcitable cells than is generally thought. Cognizance of variations in calcium-signaling motifs becomes especially important given the relationship between patterns of gene expression and specific calcium-signaling pathways. It may be useful for neuroscientists and others traditionally focusing on excitable cells to take note of developments in the rapidly evolving field of calcium signaling and calcium channels in nonexcitable cells [17].

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Copyright © 1999, American Society for Neurochemistry.
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