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• W2078227834 abstract "Cells communicate with their environment through receptor proteins on the cell membrane. Some ion channels are receptors, whereas others are linked to receptors through guanine nucleotide-binding proteins (G proteins). Ion channels control intracellular concentrations of ions such as calcium, and these concentrations control cell functions such as secretion and cell division. This review summarizes the current state of knowledge about the control of ion channels. Cells communicate with their environment through receptor proteins on the cell membrane. Some ion channels are receptors, whereas others are linked to receptors through guanine nucleotide-binding proteins (G proteins). Ion channels control intracellular concentrations of ions such as calcium, and these concentrations control cell functions such as secretion and cell division. This review summarizes the current state of knowledge about the control of ion channels. The interior of cells is insulated from the surrounding environment by a lipid bilayer, the cell membrane. The membrane is more than a simple insulator in that it contains many different receptors that enable the cell to respond to hormonal and transmitter stimuli. These receptors are primarily proteins that bind specific agonists. Molecular biologic approaches are currently being used to demonstrate the structural features of receptors. For example, the β-adrenergic receptor that binds molecules such as epinephrine has seven segments that span the thickness of the membrane and other regions that make extracellular and cytoplasmic loops. The structure of the transmembrane-spanning segments and some of the extracellular proteins selects against agents that do not resemble a β-adrenergic agonist. On the cytoplasmic side, a large loop of receptor protein recognizes the guanine nucleotide regulatory-binding protein (guanine triphosphate [GTP]-binding protein or G protein). Other sites in the cytoplasm are phosphorylated to desensitize the receptor.1Lefkowitz RJ Caron MG Adrenergic receptors: models for the study of receptors coupled to guanine nucleotide regulatory proteins.J Biol Chem. 1988; 263: 4993-4996Abstract Full Text PDF PubMed Google Scholar In this review, we discuss some of the new findings related to how interactions between receptors and G protein modulate ion channels. Ion channels, which can be considered efficient enzymes, allow only certain types of ions to flow across the cell membrane, at the rate of about 1 million ions per second per channel. In contrast to movement by pumps, such as the Na+, K+-adenosine triphosphatase pump, translocation of ions through channels does not require as much energy. The channel simply opens and allows ions to flow down a concentration gradient. The pump, however, maintains the concentration gradient. Most cells generally maintain an environment of 10 mM Na+, 140 mM K+, 100 nM Ca2+, and 10 mM CI” intracellularly and 140 mM Na+, 4 mM K+, 2 mM Ca2+, and 140 mM CI” extracellularly. Many ion channels are highly selective and allow only one type of ion to flow through the membrane. Consequently, channels are sometimes named for their selectivity—for example, Na+ channels, K+ channels, and Ca2+ channels. Transmitter-activated channels are named for the agonist that causes the channel to open; examples in this class are the nicotinic acetylcholine, glutamate, and glycine channels. These channels can also select for specific ions. Ion channels primarily control the electrical potential across the membrane. Each cell is a battery with the inside having a potential of-70 mV with respect to the outside. Inward cationic currents depolarize the cell to more positive potentials, whereas outward currents hyperpolarize the cell toward more negative potentials. The resting membrane potential approaches the equilibrium (Nernst) potential for K+ because in the steady state more K+ channels are open than other kinds of channels. When a channel opens, it helps drive the membrane potential to its equilibrium potential: for K+, −90 mV; for Na+, +55 mV; for Ca2+, +150 mV; and for CI”, −30 to −80 mV. The opening and closing of ion channels thus underlie all changes in membrane potential, including the well-known action potentials in the firing of nerves, skeletal muscle, and cardiac membranes.2Hille B Ionic Channels of Excitable Membranes. Sinauer Associates, Sunderland, Massachusetts1984Google Scholar, 3Clapham DE Potassium and tissue excitability.in: Seidin DW Giebisch G The Regulation of Potassium Balance. Raven Press, New York1989: 57-88Google Scholar In all cells, the changes in membrane potential are important signaling functions. Therefore, understanding the regulation of ion channels is critical to understanding cell signaling. Like enzymes, ion channels have regulatory sites. These sites can be on the extracellular or the intracellular side of the membrane or even within the pore of the channel. For example, one type of Ca2+ channel has three binding sites—one externally for dihydropyridines, one internally for phosphorylation sites that prolong the open state of the channel, and one within the pore that binds protons that transiently block the passage of Ca2+ ions. Because ion channels are relatively large (100 to 500 kd) in comparison with other membrane proteins, many possible regulatory sites exist. Powerful techniques in molecular biology and patch clamp electrophysiology can be used to study the methods used by the cell to regulate ion channels. We define “second-messenger systems” as means of communicating between cell surface events and effector systems such as enzymes or ion channels. One of the simplest second messengers is Ca2+, which goes directly through some ion channels and can initiate contraction by binding to various calcium-binding proteins in skeletal, smooth, or cardiac muscle. Ca2+ also directly affects many enzyme systems and ion channels. Another major class of second messengers is linked to receptors by G proteins. Agonists initiate cellular communication by binding to a receptor that is coupled to a G protein. The G protein then converts the signal message into a cascade of multiple potential second-messenger molecules. One common theme among receptors coupled to G proteins is that several second-messenger systems can be activated. This situation could prevail if a signal interacted with several different G-protein subtypes, each of which was related to a specific pathway. Alternatively, a single receptor could be coupled to a single pluripotent G protein that affects multiple second-messenger systems. Cells may also vary in the complement of effectors elicited by a single receptor. For example, somatostatin couples to three effectors in a single cell, whereas γ-aminobutyric acid B receptors (GABAB) may couple to Ca2+ channels in one cell type and to K+ channels in another cell type. The receptors that transmit and amplify signals across membranes by means of G proteins include those for β-adrenergic transmitters, muscarinic acetylcholine, somatostatin, serotonin, substance P, opiate, GABAB, dopamine, α-adrenergic transmitters, neuropeptide Y, cholecystokinin, adenosine, and rhodopsin. G proteins are composed of three subunits—α, β, and γ (Fig. 1).4Stryer L Bourne HR G proteins: a family of signal transducers.Annu Rev Cell Biol. 1986; 2: 391-419Crossref PubMed Scopus (626) Google Scholar, 5Gilman AG G proteins: transducers of receptor-generated signals.Annu Rev Biochem. 1987; 56: 615-649Crossref PubMed Scopus (4711) Google Scholar, 6Neer EJ Clapham DE Roles of G protein subunits in transmembrane signalling.Nature. 1988; 333: 129-134Crossref PubMed Scopus (558) Google Scholar In the resting state, the α subunit is normally bound to guanine diphosphate (GDP). When the receptor binds an agonist, GTP replaces GDP on the α subunit. When it has GTP bound to it, the α subunit has a lower affinity for the βγ subunits and probably dissociates from βγ (β and γ subunits are not separable except by denaturing methods, and their independent functions are unknown). When bound to GTP, the α subunit is “activated” and can modulate various effectors. The clearest example is the activation of adenylyl cyclase by a-GTP to increase the production of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Recently, the βγ subunit was also shown to be an activator of a K+ channel and an enzyme.7Logothetis DE Kurachi Y Galper J Neer EJ Clapham DE The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart.Nature. 1987; 325: 321-326Crossref PubMed Scopus (876) Google Scholar, 8Jelsema CL Axelrod J Stimulation of phospholipase activity in bovine rod outer segments by the βγ subunits of transducin and its inhibition by the α subunit.Proc Natl Acad Sei U S A. 1987; 84: 3623-3627Crossref PubMed Scopus (265) Google Scholar The α subunit has intrinsic GTPase activity and converts GTP to GDP; thus, reassociation with βγ is possible, and the cycle of events can be turned off. This system not only amplifies the receptor binding step but also adds substantially to the regulatory possibilities. The availability of the α subunit can be affected by Mg2+, GTP, and the βγ subunit. Furthermore, phosphorylation sites may exist on the α subunit itself. If the βγ subunit is an activator and also binds the α subunit to turn off the α activity, the potential consequences of G-protein activation are multiplied. Modulation of the βγ subunit and the dissociation of β and γ are possibilities that have not yet been investigated. In the past few years, the information about G proteins and receptors that bind G proteins has vastly expanded. With the use of techniques in molecular biology, 17 types of α subunits, based on purification and cloning sequences, have been described. The prior nomenclature based on interaction with the cyclase system (αs for the adenylyl cyclase stimulatory subunit and α for the inhibitory subunit; see subsequent discussion) is inadequate. In fact, it will be several years before the functions of all the α subunits are known. Four types of β subunits have been cloned,9Fong HKW Amatruda III, TT Birren BW Simon MI Distinct forms of the β subunit of GTP-binding regulatory proteins identified by molecular cloning.Proc Natl Acad Sei U S A. 1987; 84: 3792-3796Crossref PubMed Scopus (126) Google Scholar and evidence is available for three γ subunits. Less is known about the functions of the β and γ subunits than about the α subunits. Despite these uncertainties, the β-adrenergic and muscarinic acetylcholine receptors clearly have binding sites for G proteins on their intracellular surfaces. Probably many more receptors will be found that follow the pattern of the seven transmembrane-spanning segments with a cytoplasmic loop for G-protein interaction. The structure of the oc subunits is now being investigated,10Masters SB Sullivan KA Miller RT Beiderman B Lopez NG Ramachandran J Bourne HR Carboxyl terminal domain of Gsα specifies coupling of receptors to stimulation adenylyl cyclase.Science. 1988; 241: 448-451Crossref PubMed Scopus (104) Google Scholar and the receptor binding, GTP-binding, and effector regions of the α subunit may soon be clearly defined. Other issues for future research include determination of the uniqueness of the effector and receptor binding regions, which would affect whether the α subunits may be interchanged and how the specificity of receptor binding is translated into specific or nonspecific interactions with effectors.6Neer EJ Clapham DE Roles of G protein subunits in transmembrane signalling.Nature. 1988; 333: 129-134Crossref PubMed Scopus (558) Google Scholar Two well-characterized second-messenger systems activated through G proteins are shown in Figure 2. When a β-adrenergic agonist binds to the stimulatory receptor, the stimulatory G protein (Gs protein) α subunit activates the catalytic subunit of adenylyl cyclase (Fig. 2 α). cAMP is then formed from ATP. cAMP, a classic second messenger, has been shown to perform many functions in cells. For example, cAMP may bind to the regulatory subunit of protein kinase A; hence, the catalytic subunit can phosphorylate various serine and threonine residues of effector proteins. One such protein is the L-type Ca2+ channel in which phosphorylation increases the opening of the channel. This mechanism is one way in which β-adrenergic receptor binding increases the Ca2+ current in ventricular heart cells and augments contractility. Adenylyl cyclase is inhibited through another G protein, G;. Three types of pertussis toxin-sensitive Gi α subunits have been described. Active Gi. inhibits cyclase, either through direct binding of the α subunit to the catalytic subunit of adenylyl cyclase or by binding of βγ to the αs subunit, and thus antagonizes β-adrenergic agonists. The family of receptors that transduce their signals through pertussis toxin-sensitive Gi proteins includes muscarinic (m2), somatostatin, enkephalin, adenosine (A1), GABAB, D2-dopamine, and a2-adrenergic receptors. All these transmitters inhibit Ca2+ channels, stimulate inward-rectifying K+ channels, and are negatively coupled to adenylyl cyclase. These receptors illustrate the pluripotent nature of receptor signaling through G proteins. Another second-messenger system, the phosphatidylinositol pathway, is shown in Figure 2 b. Phosphoinositides (or phosphatidylinositols) are minor components of all eukaryotic cell membranes. Research during the past 10 years has indicated that the inositol-containing phospholipids play important roles in the transduction of extracellular signals through cell surface receptors to cause various cellular responses.11Berridge MJ Inositol trisphosphate and diacylglycerol as second messengers.Biochem J. 1984; 220: 345-360Crossref PubMed Scopus (2490) Google Scholar Hm1 and Hm3 muscarinic acetylcholine,12Peralta EG Ashkenazi A Winslow JW Ramachandran J Capon DJ Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes.Nature. 1988; 334: 434-437Crossref PubMed Scopus (548) Google Scholar α-adrenergic transmitters, substance P, angiotensin II, thyrotropin releasing hormone, and thyroid-stimulating hormone receptors all are coupled to turnover of phosphatidylinositol. Many other hormones, neurotransmitters, and peptide growth factors also initiate the breakdown of phosphoinositides. The events after occupancy of the receptor by an agonist are shown in Figure 2 b. When an agonist binds to the receptor, an activated G protein stimulates phospholipase C, an action that results in the breakdown of phosphoinositides to diacylglycerol and inositol triphosphate.13Majerus PW Connolly TM Deckmyn H Ross TS Bross TE Ishii H Bansal VS Wilson DB The metabolism of phosphoinositide-derived messenger molecules.Science. 1986; 234: 1519-1526Crossref PubMed Scopus (474) Google Scholar These products are now considered second messengers and have many important effects on cell function. Diacylglycerol stimulates protein kinase C, an enzyme that is capable of phosphorylating certain proteins in the cell membrane.14Nishizuka Y The role of protein kinase C in cell surface signal transduction and tumour promotion.Nature. 1984; 308: 693-698Crossref PubMed Scopus (5757) Google Scholar Through phosphorylation of membrane proteins, protein kinase C regulates various types of ion channels and also the receptor affinities for specific ligands and cell growth. Inositol triphosphate causes release of Ca2+ from the endoplasmic reticulum into the cytosol and thus increases the cytosolie Ca2+ concentration.15Berridge MJ Irvine RF Inositol trisphosphate, a novel second messenger in cellular signal transduction.Nature. 1984; 312: 315-321Crossref PubMed Scopus (4246) Google Scholar This increase in cytosolie Ca2+ regulates ion channel conductance, Ca2+-dependent enzyme activities, contraction, secretion, release of neurotransmitters, and exocytosis. Inositol triphosphate can also be phosphorylated to form inositol tetraphosphate. Recent studies suggest that inositol tetraphosphate may also act as a second messenger to increase Ca2+ entry into sea urchin eggs16Irvine RF Moor RM Microinjection of inositol 1,3,4,5-tetrakisphosphate activates sea urchin eggs by a mechanism dependent on external Ca2+.Biochem J. 1986; 240: 917-920Crossref PubMed Scopus (476) Google Scholar and synergize with inositol triphosphate to stimulate Ca2+-activated K+ currents.17Morris AP Gallacher DV Irvine RF Petersen OH Synergism of inositol trisphosphate and tetrakisphosphate in activating Ca2+-dependent K+ channels.Nature. 1987; 330: 653-655Crossref PubMed Scopus (343) Google Scholar Recent investigative studies have also revealed that inositol tetraphosphate can be produced from phosphatidylinositol triphosphate.18Traynor-Kaplan AE Harris AL Thompson BL Taylor P Sklar LA An inositol tetrakisphosphate-containing phospholipid in activated neutrophils.Nature. 1988; 334: 353-356Crossref PubMed Scopus (210) Google Scholar Inositol triphosphate is degraded to inositol diphosphate and then to the monophosphate form by the sequential removal of a phosphate group. Inositol monophosphate is then converted to inositol, which is used for the resynthesis of phosphoinositides. Lithium, an agent used in the treatment of manic-depressive illness, inhibits synthesis of the phosphoinositides by limiting the availability of inositol. (Whether the therapeutic potential of lithium is due to this action is still being debated.) Diacylglycerol is hydrolyzed by lipases to arachidonic acid and glycerol or is phosphorylated by a kinase to form phosphatidic acid, which is used for the synthesis of phosphoinositides. Phosphatidic acid can also be synthesized de novo from glycerol and fatty acids. In addition to the G proteins that are coupled to the phosphoinositide cascade, certain G proteins are coupled to phospholipase A2.19Axelrod J Burch RM Jelsema CL Receptor-mediated activation of phospholipase via GTP-binding proteins: arachidonic acid and its metabolites as second messengers.Trends Neurosci. 1988; 11: 117-123Abstract Full Text PDF PubMed Scopus (428) Google Scholar Receptor-mediated activation of phospholipase A2 through a G protein results in the formation of arachidonic acid and lysophospholipid. Free arachidonic acid itself has been reported to activate protein kinase C directly. Some receptors that are coupled to phospholipase A2 are those for GABAB, bradykinin, vasoactive intestinal peptide, histamine, α1-adrenergic transmitters, and rhodopsin. Arachidonic acid can be generated by two other pathways: (1) the action of diacylglyceride lipase on diacylglycerol and (2) the sequential actions of phospholipase A1 and lysophospholipase. The metabolites of arachidonic acid act as second messengers for several extracellular stimuli. Arachidonic acid is a substrate for cyclooxygenase and lipoxygenase, the two major enzymes in the mammalian cells that degrade arachidonic acid.20Needleman P Turk J Jakschik BA Morrison AR Lefkowith JB Arachidonic acid metabolism.Annu Rev Biochem. 1986; 55: 69-102Crossref PubMed Google Scholar Arachidonic acid metabolites produced by the cyclooxygenase pathway are called prostaglandins. The prostaglandins produce a wide range of biologic effects in all organs of the body. Inhibition of cyclooxygenase by indomethacin has anti-inflammatory, antipyretic, and analgesic effects. The arachidonic acid metabolites formed through the lipoxygenase pathway are hydroperoxyeicosatetraenoic acid (HPETE), hydroxyeicosatetraenoic acid (HETE), leukotrienes, and lipoxins.21Parker CW Lipid mediators produced through the lipoxygenase pathway.Annu Rev Immunol. 1987; 5: 65-84Crossref PubMed Scopus (103) Google Scholar Recent studies suggest that these metabolites also act as second messengers. For example, 12-HPETE reportedly mimics the effect of FMRFamide, an agonist that produces presynaptic inhibition of transmitter release in sensory neurons of Aplysia.22Piomelli D Volterra A Dale N Siegelbaum SA Kandel ER Schwartz JH Belardetti F Lipoxygenase metabolites of archidonic acid as second messengers for presynaptic inhibition of Aplysia sensory cells.Nature. 1987; 328: 38-43Crossref PubMed Scopus (506) Google Scholar Leukotrienes also cause changes in vascular permeability. In addition to the second-messenger role of arachidonic acid and metabolites inside the cell, these lipophilic molecules might also diffuse out of the cell and activate surface receptors on neighboring cells. We have only scratched the surface of the many regulatory systems to be described and the many more yet to be discovered. In the subsequent section, we discuss how the pathways we have described regulate ion channels. For an excellent review of receptor coupling to ion channels in brain, see the article by Nicoll.23Nicoll RA The coupling of neurotransmitter receptors to ion channels in the brain.Science. 1988; 241: 545-551Crossref PubMed Scopus (448) Google Scholar Cationic flow into the cell depolarizes the cell. Two major kinds of cation-selective channels pass current, usually in the inward direction (because of the ion gradients under physiologic conditions): the Na+ channels responsible for the fast upstroke of action potentials and the Ca2+ channels responsible for the contraction of muscle cells. The fast Na+ channel classically associated with the fast upstroke of action potentials is probably a family of structurally related proteins. The tetrodotoxin-sensitive Na+ channel does not seem to be highly regulated by the cell because the channels are so stable that they can be purified from native membranes and placed into lipid bilayers with little disturbance in their voltage gating. Nonetheless, cAMP-dependent protein kinase catalyzes the incorporation of phosphate into the channel,24Rossie S Gordon D Catterall WA Identification of an intracellular domain of the sodium channel having multiple cAMP-dependent phosphorylation sites.J Biol Chem. 1987; 262: 17530-17535Abstract Full Text PDF PubMed Google Scholar presumably to regulate its function. Less is known about the regulation of the Na+-selective amiloride-sensitive channel in epithelial cells. Several types of voltage-dependent Ca2+ channels have been described.25Nowycky MC Fox AP Tsien RW Three types of neuronal calcium channel with different calcium agonist sensitivity.Nature. 1985; 316: 440-443Crossref PubMed Scopus (1607) Google Scholar The L-type channel conducts a sustained or noninactivating current, is activated at more positive membrane potentials, and is sensitive to the dihydropyridines (Fig. 3 a). The N-type channel conducts an inactivating current, is activated at intermediate membrane potentials, and is insensitive to the dihydropyridines. The T-type channel conducts a rapidly inactivating current, is activated at more negative membrane potentials, and is insensitive to the dihydropyridines. Receptors That Inhibit Ca2+ Channels.—Somatostatin is coupled to a pertussis toxin-sensitive G protein that inhibits the L-type Ca2+ current independent of its inhibitory effect on adenylyl cyclase in the AtT-20 pituitary cell line26Lewis DL Weight FF Luini A A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line.Proc Natl Acad Sei U S A. 1986; 83: 9035-9039Crossref PubMed Scopus (176) Google Scholar (Table 1). Stimulation of δ opiate receptors also inhibits Ca2+ currents in NG108-15 neuroblastoma-glioma cells.27Tsunoo A Yoshii M Narahashi T Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glioma hybrid NG108-15 cells.Proc Natl Acad Sei U S A. 1986; 83: 9832-9836Crossref PubMed Scopus (177) Google Scholar This effect is sensitive to pertussis toxin and can be reconstituted by intracellular dialysis with Go or Gi (both pertussis toxin-sensitive G proteins).28Hescheler J Rosenthal W Trautwein W Schultz G The GTP-binding protein, Go, regulates neuronal calcium channels.Nature. 1987; 325: 445-447Crossref PubMed Scopus (644) Google ScholarTable 1Receptors and Their Effects on Calcium Ion Currents, Inward-Rectifier Potassium Ion Currents, and Adenylyl Cyclase Through G Proteins Sensitive to Pertussis or Cholera Toxin*GABAB = B receptor of γ-aminobutyric acid; ICa = calcium ion currents; IK.IR = inward-rectifier potassium ion currents.ReceptorICaIK.IRAdenylyl cyclaseToxinβ-Norepinephrine↑?↑Choleraα2-Norepinephrine↓↑↓PertussisSomatostatin↓↑↓PertussisEnkephalin↓↑?PertussisGABAB↓?↓PertussisDopamine↓↑?PertussisMuscarinic acetylcholine↓↑↓PertussisNeuropeptide Y↓??PertussisAdenosine↓↑?PertussisCholecystokinin↓???Atrial natriuretic factor↓???Angiotensin II↑?↓PertussisLuteinizing hormone releasing hormone↑??Pertussis* GABAB = B receptor of γ-aminobutyric acid; ICa = calcium ion currents; IK.IR = inward-rectifier potassium ion currents. Open table in a new tab Activation of the GABAB receptor inhibits the L-type Ca2+ current in rat or chick dorsal root ganglion neurons.29Deisz RA Lux HD γ-Aminobutyric acid-induced depression of calcium currents of chick sensory neurons.Neurosci Lett. 1985; 56: 205-210Crossref PubMed Scopus (114) Google Scholar, 30Holz IV, GG Rane SG Dunlap K GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels.Nature. 1986; 319: 670-672Crossref PubMed Scopus (468) Google Scholar, 31Dolphin AC Scott RH Calcium channel currents and their inhibition by (-)-baclofen in rat sensory neurones: modulation by guanine nucleotides.J Physiol (Lond). 1987; 386: 1-17Google Scholar Conversely, GABAB increases K+ conductance but has no effect on Ca2+ conductance in hippocampal cells.32Newberry NR Nicoll RA Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells.Nature. 1984; 308: 450-452Crossref PubMed Scopus (254) Google Scholar Investigators have suggested that GABAB receptors may couple to phospholipase A2, which may, in turn, affect the activity of adenylyl cyclase and channels through arachidonic acid.33Bormann J Electrophysiology of GABAA and GABAB receptor subtypes.Trends Neurosci. 1988; 11: 112-116Abstract Full Text PDF PubMed Scopus (568) Google Scholar, 34Enna SJ Karbon EW Receptor regulation: evidence for a relationship between phospholipid metabolism and neurotransmitter receptor-mediated cAMP formation in brain.Trends Pharmacol Sei. 1987; 8: 21-24Abstract Full Text PDF Scopus (63) Google Scholar In cardiac cells, the m2 muscarinic receptor inhibits Ca2+ current by a mechanism that involves G protein-mediated inhibition of adenylyl cyclase activity.35Fischmeister R Hartzell HC Mechanism of action of acetylcholine on calcium current in single cells from frog ventricle.J Physiol (Lond). 1986; 376: 183-202Google Scholar, 36Breitwieser GE Szabo G Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue.Nature. 1985; 317: 538-540Crossref PubMed Scopus (357) Google Scholar Activation of a pharmacologically defined ml muscarinic receptor in rat superior cervical ganglion neurons inhibits a rapidly inactivating N-type Ca2+ channel. This effect is sensitive to pertussis toxin, mimicked by guanosine 5′-O-thiotriphosphate (GTPγS), and independent of the adenylyl cyclase-protein kinase A or C pathway.37Wanke E Ferroni A Malgaroli A Ambrosini A Pozzan T Meldolesi J Activation of a muscarinic receptor selectively inhibits a rapidly inactivated Ca2+ current in rat sympathetic neurons.Proc Natl Acad Sei U S A. 1987; 84: 4313-4317Crossref PubMed Scopus (202) Google Scholar Atrial natriuretic factor inhibits cardiac Ca2+ current after stimulation of the β-adrenergic receptor—probably by increasing cyclic guanine monophosphate (cGMP), which in turn mediates the hydrolysis of cAMP by a cGMP-activated cyclic nucleotide phosphodiesterase.38Hartzell HC Fischmeister R Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells.Nature. 1986; 323: 273-275Crossref PubMed Scopus (249) Google Scholar, 39Gisbert M-P Fischmeister R Atrial natriuretic factor regulates the calcium current in frog isolated cardiac cells.Circ Res. 1988; 62: 660-667Crossref PubMed Scopus (58) Google Scholar Atrial natriuretic factor has also been reported to inhibit a T-type Ca2+ current in bovine adrenal glomerulosa cells.40McCarthy RT Rasmussen H Barrett PQ Effects of atrial natriuretic factor on calcium channel currents in bovine adrenal glomerulosa cells (abstract).Biophys J. 1988; 53: 557aGoogle Scholar Dopamine inhibits both T- and L-type Ca2+ currents in chick dorsal root and sympathetic ganglion neurons.41Marchetti C Carbone E Lux HD Effects of dopamine and noradrenaline on Ca channels of cultured sensory and sympathetic neurons of chick.Pflugers Arch. 1986; 406: 104-111Crossref PubMed Scopus (237) Google Scholar In Helix neurons, however, dopamine increases the Ca2+ current; this response involves a 40-kd α subunit that is recognized by mammalian brain anti-αo, the α subunit of Go (39 kd). Injection of mammalian brain αo mimics the dopamine effect, and injection of anti-αo blocks the effect, results that suggest that αo mediates the effect of dopamine on Ca2+ currents.42Harris-Warrick RM Hammond C Paupardin-Tritsch D Homburger V Rouot B Bockaert J Gerschenfeld HM An α40 subunit of a GTP-binding protein immunologically related to Go mediates a dopamine-induced decrease of Ca2+ current in small neurons.Neuron. 1988; 1: 27-32Abstract Full Text PDF PubMed Scopus (90) Google Scholar Adenosine inhibits the Ca2+ current in mouse and rat dorsal root ganglion neurons.43Macdonald RL Skerritt JH Werz MA Adenosine agonists reduce voltage-dependent calcium conductance of mouse sensory neurones in cell culture.J Physiol (Lond). 1986; 370: 75-90Google Scholar, 44Dolphin AC Forda SR Scott RH Calcium-dependent currents in cultured rat d" @default.
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• W2078227834 title "Intracellular Regulation of Ion Channels in Cell Membranes" @default.
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