Mediation of intracellular calcium: Variances on a common theme (original) (raw)
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Calcium binding proteins and cellular regulation
Life Sciences, 1982
An important feature of cellular regulation is the precise control of intracellular calcium levels. This is accomplished both by dynamic organelle release and sequestration of calcium and by specific calcium active transport mechanisms located in the plasma membrane. The actual calcium signal for mediation of a cellular response is ca'rried out by specific intracellular proteins, the most widely studied examples are calmodulln and troponin C. The recent discovery of phospholipid protein kinase and calcimedins suggests receptor mediation via several independent proteins. The physiological importance of a particular protein as a calcium messenger rests on several features: 1) calcium binding is of the order of 1-10 pm, 2) the protein is known to be localized at the site of proposed action, 3) if translocation occurs upon activation, the time required is consistent with the time course of the physiologic response and 4) substrates or effectors at the next level of action when isolated can be demonstrated to have similar activation kinetics as in situ. Regulation of Cell Function Calcium plays a central role in the regulation of a wide range of cellular functions (1,2). Parathyroid hormone secretion is calcium dependent (3). The induction of mitogenic effects of lectins with both chick fibroblasts (4) and lymphocytes (5) requires calcium. Adhesion of cells to solid substrates is influenced by calcium; adhesion appears to be calcium independent but stabilization of adhesion to the plating surface is dependent on calcium levels (6). Calcium is also known to in~uence microtubule assembly and disassembly (7), exocytosis of homones and secretory products and neurotransmitter release at synapses (8). Alterations in calcium levels may also initiate developmental processes since a rapid rise in free intracellular calcium occurs with fertilization in fish eggs (9). Calcium
Calcium-Binding Proteins: Intracellular Sensors from the Calmodulin Superfamily
Biochemical and Biophysical Research Communications, 2002
In all eukaryotic cells, and particularly in neurons, Ca 2؉ ions are important second messengers in a variety of cellular signaling pathways. In the retina, Ca 2؉ modulation plays a crucial function in the development of the visual system's neuronal connectivity and a regulatory role in the conversion of the light signal received by photoreceptors into an electrical signal transmitted to the brain. Therefore, the study of retinal Ca 2؉ -binding proteins, which frequently mediate Ca 2؉ signaling, has given rise to the important discovery of two subfamilies of these proteins, neuronal Ca 2؉ -binding proteins (NCBPs) and calcium-binding proteins (CaBPs), that display similarities to calmodulin (CaM). These and other Ca 2؉ -binding proteins are integral components of cellular events controlled by Ca 2؉ . Some members of these subfamilies also play a vital role in signal transduction outside of the retina. The expansion of the CaM-like protein family reveals diversification among Ca 2؉ -binding proteins that evolved on the basis of the classic molecule, CaM. A large number of NCBP and CaBP subfamily members would benefit from their potentially specialized role in Ca 2؉ -dependent cellular processes. Pinpointing the role of these proteins will be a challenging task for further research.
Biosystems, 1980
Phosphorylase ki~tase, (aj3T~)4, binds in two subsequent steps 2 tool Ca2"/monomer (a~T6) to high affinity sites, NI,, and 1-2 mol to low affinity sites, N2. Analogously, the holotroponin TI,C binds 2 tool Ca 2" to high affinity and further 2 mol to low affinity sites. In both protein complexes Ca 2" binds to one specific subunit: in phosphorylase kinase to the 5-and in troponin TI2C to the C-subunit. In both proteins the high affinity sites show Ca~'-Mg 2' competition. Cooperative interactions are observable at the low affinity Mg 2" inducible sites in phosphorylase kinase and at the high affinity sites in troponin. The isolat~l 8 subunit binds 2 tool Ca 2+ with low affinity in a positive cooperative manner. Ca ~ binding to the high affinity sites inhibits the phosphorylation of the I subunits of troponin but stimulates that of the a and #8 subunits of phosphorylase kivmse. Phosphorylase kinase exhibits three partial activities: A0, A1 and A2. A0 is Ca 2÷ independent whereas activation of Al can be correlated to Ca 2' binding to the sites, Nla, and activation of A2 with Ca 2÷ binding to the sites, N2. Both Ca ~'" binding proteins, ~ and troponin C, can activate the kinase activity of calsequestrin which is a membrane component of the sarcoplasmic reticulum.
During the last 2 years, our laboratory has worked on the elucidation of the molecular basis of capacita-tive calcium entry (CCE) into cells. Specifically, we tested the hypothesis that CCE channels are formed of subunits encoded in genes related to the Drosophila trp gene. The first step in this pursuit was to search for mammalian trp genes. We found not one but six mammalian genes and cloned several of their cDNAs, some in their full length. As assayed in mammalian cells, overexpression of some mammalian Trps increases CCE, while expression of partial trp cDNAs in antisense orientation can interfere with endogenous CCE. These findings provided a firm connection between CCE and mammalian Trps. This article reviews the known forms of CCE and highlights unanswered questions in our understanding of intracellular Ca 2 homeostasis and the physiological roles of CCE. The two primary second messengers mediating rapid responses of cells to hormones, autacoids, and neurotransmitters are cyclic nucleotides and Ca 2. Cyclic nucleotides act, for the most part, by activating protein kinases. The actions of Ca 2 are more complex, in that this cation acts in two ways: directly, by binding to effector proteins, and indirectly, by first binding to regulatory proteins such as calmodulin, troponin C, and recoverin, which in turn associate and modulate effector proteins. Effector proteins regulated in these manners by Ca 2 include not only protein kinases and protein phosphatases but also phospholipases and adenylyl cyclases, which are signaling enzymes in their own right, and an array of proteins involved in cellular responses that range from muscle contraction to glycogenolysis, endo-, exo-, and neurosecretion, cell differentiation , and programmed cell death. A common mechanism used by hormones and growth factors to signal through cytosolic Ca 2 ([Ca 2 ] i) is activation of a rather complex reaction cascade that begins with stimulation of phosphoi-nositide-specific phospholipase C (PLC) enzymes, PLC and PLC, and is followed sequentially by formation of
Calcium signaling in physiology and pathophysiology
Acta Pharmacologica Sinica, 2006
Calcium ions are the most ubiquitous and pluripotent cellular signaling molecules that control a wide variety of cellular processes. The calcium signaling system is represented by a relatively limited number of highly conserved transporters and channels, which execute Ca 2+ movements across biological membranes and by many thousands of Ca 2+ -sensitive effectors. Molecular cascades, responsible for the generation of calcium signals, are tightly controlled by Ca 2+ ions themselves and by genetic factors, which tune the expression of different Ca 2+ -handling molecules according to adaptational requirements. Ca 2+ ions determine normal physiological reactions and the development of many pathological processes.
Journal of Biological Chemistry, 2002
1 The abbreviations used are: ER, endoplasmic reticulum; SOC, store operated channels; SOCE, store operated calcium entry; RNAi, RNA interference; dsRNA, double stranded RNA; IP 3 , inositol 1,4,5-trisphosphate; IP 3 R, inositol trisphosphate receptor; TRP, transient receptor potential channel; IFI, initial fluorescence increment; Bk2R, human bradykinin type II receptor; Bk, bradykinin; TG, thapsigargin; TFP, trifluoperazine maleate; CHO, Chinese hamster ovary; PBS, phosphate-buffered saline; P o , open probability.
Journal of Biological Chemistry, 2005
1 The abbreviations used are: trp, transient receptor potential; CaM, calmodulin; Bk, bradykinin; Bk2R, bradykinin receptor type 2; CBII, second CaM binding; CHO, Chinese hamster ovary; CIRB, CaM/IP 3 R binding; H1R, histamine receptor type 1; HEK, human embryonic kidney; IP 3 R, inositol 1,4,5-trisphosphate receptor; MBP, maltose-binding protein; mTRPC5, mouse canonical transient receptor potential 5; TRPL, TRP-like; W7, N-aminohexyl-5-chloro-1-naphthalenesulfonamide; TFP, trifluoperazine dimaleate; RT, reverse transcription; HEDTA, N-(2-hydroxyethyl)ethylenediaminetriacetic acid.