Calcium-dependent intracellular

Stimulation of the neuron lea ding to electrical activation of the nerve terminal in a physiologically relevant manner should eUcit a calcium-dependent release of the neurotransmitter. Although release is dependent on extracellular calcium, intracellular calcium homeostasis may also modulate the process. Neurotransmitter release that is independent of extracellular calcium is usually artifactual, or in some cases may represent release from a non-neuronal sources such as gha (3). 

In addition to intracellular heme-containing proteins, big-conductance calcium-dependent K+ (BKCa) channels and calcium-spark activated transient Kca channels in plasma membrane are also tar geted by CO [3]. As well known, nitric oxide (NO) also activates BKca channels in vascular smooth muscle cells. While both NO and CO open BKCa channels, CO mainly acts on alpha subunit of BKCa channels and NO mainly acts on beta subunit of BKca channels in vascular smooth muscle cells. Rather than a redundant machinery, CO and NO provide a coordinated regulation of BKca channel function by acting on different subunits of the same protein complex. Furthermore, pretreatment of vascular smooth muscle... 

The action of a peptidase can be neutralized by an inhibitor. Some inhibitors are very broad in their action and are capable of inhibiting many different peptidases, including peptidases of different catalytic types. Some inhibitors are assumed to be specific for a particular catalytic type, but can inhibit peptidases of different types. Leupeptin, for example, is widely used as an inhibitor of serine peptidases from family SI, but it is also known to inhibit cysteine peptidases from family Cl. Cysteine pqrtidase inhibitors such as iodoacetic acid interact with the thiol of the catalytic cysteine. However, this reduction can occur on any thiol group and can affect other, predominantly intracellular, peptidases with a thiol dependency. One example is thimet oligopepti-dase. Metal chelators such as EDTA can inhibit meta-llopeptidases, but can also affect peptidases that have a requirement for metal ions that is indq>endent of their catalytic activity, such as the calcium-dependent cysteine endopqrtidase calpain 1. 

As with the effects of oxidant stress on the calcium channel, part of the change in the steady-state background current could also be attributed to an indirect effect secondary to the elevation of intracellular calcium (Matsuura and Shattock, 1991b). However, oxidant stress also exerted a direct effect on the inward rectifying potassium current (7ki). The combination of an inhibition of 7ki and the activation of a calcium-dependent current are likely to contribute to the prolongation of the action potential duration and the increased susceptibility... 

In many cells, phosphoinositide signaling leads to an elevation in intracellular calcium levels through the release of calcium from intracellular stores in response to IP3-dependent gating of channels in the endoplasmic epithelium (Ch. 20). It is not known if IP3 plays a critical role in TRC transduction, but such a role would be consistent with recent findings that a Ca2+-activated cation channel, TRPM5, is essential for normal sweet, bitter and umami taste function [49,66-69],... 

During the last ten years, it has become apparent that calcium-dependent papain-like peptidases called calpains (EC 3.4.22.17) represent an important intracellular nonlysosomal enzyme system [35][36], These enzymes show limited proteolytic activity at neutral pH and are present in virtually every eukaryotic cell type. They have been found to function in specific proteolytic events that alter intracellular metabolism and structure, rather than in general turnover of intracellular proteins. Calpains are composed of two nonidentical subunits, each of which contains functional calcium-binding sites. Two types of calpains, i.e., /i-calpain and m-calpain (formerly calpain I and calpain II, respectively), have been identified that differ in their Ca2+ requirement for activation. The activity of calpains is regulated by intracellular Ca2+ levels. At elevated cytoplasmic calcium concentrations, the precursor procal-pain associates with the inner surface of the cell membrane. This interaction seems to trigger autoproteolysis of procalpain, and active calpain is released into the cytoplasm [37]. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

The mechanisms described so far are synoptically summarized in figure 13. An important point to mention is that, as already said, the affection of the gap junction conductance is not mono- but multicausal under the most physiological and pathophysiological conditions due to the interactions between the intracellular mediators. Thus, most processes will affect intracellular calcium and, on the other hand, a change in intracellular calcium will activate a variety of intracellular mechanisms and affect the activity of many calcium-dependent enzymes. 

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