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PubMed2006

Expression of potassium channel isoforms mRNA in normal human adrenals and aldosterone-secreting adenomas.

Increased aldosterone secretion has been found in a mouse lacking the KCNE1 gene which codes for a regulatory protein of the KCNQ1 gene product, forming the channel for the outward rectifying delayed K+ current. Abnormalities in proteins regulating the K+ fluxes across membranes may be responsible for aldosterone-secreting adenomas (aldosteronomas) also because K+ channels are involved in cell growth. Normal and adenomatous adrenal samples and NCI-H295 cell line were used to: a) evaluate KCNE1 and KCNQ1 gene expression, b) sequence the full length cDNAs of KCNE1 and both KCNQ1 isoforms. These differently spliced KCNE1 and KCNQ1 mRNAs were expressed in adrenal tissue. In contrast, KCNQ1 isoform 2 mRNA was not expressed in kidney control tissues and NCl-H295 cell line. NCI-H295 cell line also had a significantly lower expression of KCNQ1 isoform 1 mRNA than normal adrenals and aldosteronomas. We did not find any somatic mutations in the coding sequences of both genes. This different expression pattern of KCNQ1 isoforms in NCI-H295 cell line with the lack of the mRNA for the dominant-negative KCNQ1 isoform 2 supports the involvement of voltage-gated K+ channel in cell proliferation.

Adenoma↗
PubMed1998

Somatodendritic depolarization-activated potassium currents in rat neostriatal cholinergic interneurons are predominantly of the A type and attributable to coexpression of Kv4.2 and Kv4.1 subunits.

Unlike other neostriatal neurons, cholinergic interneurons exhibit spontaneous, low-frequency, repetitive firing. To gain an understanding of the K+ channels regulating this behavior, acutely isolated adult rat cholinergic interneurons were studied using whole-cell voltage-clamp and single-cell reverse transcription-PCR techniques. Cholinergic interneurons were identified by the presence of choline acetyltransferase (ChAT) mRNA. Depolarization-activated potassium currents in cholinergic interneurons were dominated by a rapidly inactivating, K+-selective A current that became active at subthreshold potentials. Depolarizing prepulses inactivated this component of the current, leaving a delayed, rectifier-like current. Micromolar concentrations of Cd2+ dramatically shifted the voltage dependence of the A current without significantly affecting the delayed rectifier. The A-channel antagonist 4-aminopyridine (4-AP) produced a voltage-dependent block (IC50, approximately 1 mM) with a prominent crossover at millimolar concentrations. On the other hand, TEA preferentially blocked the sustained current component at concentrations <10 mM. Single-cell mRNA profiling of subunits known to give rise to rapidly inactivating K+ currents revealed the coexpression of Kv4.1, Kv4.2, and Kv1.4 mRNAs but low or undetectable levels of Kv4.3 and Kv3.4 mRNAs. Kv1.1, beta1, and beta2 subunit mRNAs, but not beta3, were also commonly detected. The inactivation recovery kinetics of the A-type current were found to match those of Kv4.2 and 4.1 channels and not those of Kv1.4 or Kv1. 1 and beta1 channels. Immunocytochemical analysis confirmed the presence of Kv4.2 but not Kv1.4 subunits in the somatodendritic membrane of ChAT-immunoreactive neurons. These results argue that the depolarization-activated somatodendritic K+ currents in cholinergic interneurons are dominated by Kv4.2- and Kv4. 1-containing channels. The properties of these channels are consistent with their playing a prominent role in governing the slow, repetitive discharge of interneurons seen in vivo.

4-Aminopyridine↗
PubMed2004

Inhibitory effects of berberine on ion channels of rat hepatocytes.

AIM: To examine the effects of berberine, an isoquinoline alkaloid with a long history used as a tonic remedy for liver and heart, on ion channels of isolated rat hepatocytes. METHODS: Tight-seal whole-cell patch-clamp techniques were performed to investigate the effects of berberine on the delayed outward potassium currents (I(K)), inward rectifier potassium currents (I(K1)) and Ca(2+) release-activated Ca(2+) currents (I(CRAC)) in enzymatically isolated rat hepatocytes. RESULTS: Berberine 1-300 micromol/L reduced I(K) in a concentration-dependent manner with EC(50) of 38.86+/-5.37 micromol/L and n(H) of 0.82+/-0.05 (n = 8). When the bath solution was changed to tetraethylammonium (TEA) 8 mmol/L, I(K) was inhibited. Berberine 30 micromol/L reduced I(K) at all examined membrane potentials, especially at potentials positive to +60 mV (n = 8, P<0.05 or P<0.01 vs control). Berberine had mild inhibitory effects on I(K1) in rat hepatocytes. Berberine 1-300 micromol/L also inhibited I(CRAC) in a concentration-dependent fashion. The fitting parameters were EC(50) = 47.20+/-10.86 micromol/L, n(H) = 0.71+/-0.09 (n = 8). The peak value of I(CRAC) in the I-V relationship was decreased by berberine 30 micromol/L at potential negative to -80 mV (n = 8, P<0.05 vs control). But the reverse potential of I(CRAC) occurred at voltage 0 mV in all cells. CONCLUSION: Berberine has inhibitory effects on potassium and calcium currents in isolated rat hepatocytes, which may be involved in hepatoprotection.

Animals↗
PubMed2000

KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel.

Mutations in HERG and KCNQ1 (or KVLQT1) genes cause the life-threatening Long QT syndrome. These genes encode K(+) channel pore-forming subunits that associate with ancillary subunits from the KCNE family to underlie the two components, I(Kr) and I(Ks), of the human cardiac delayed rectifier current I(K). The KCNE family comprises at least three members. KCNE1 (IsK or MinK) recapitulates I(Ks) when associated with KCNQ1, whereas it augments the amplitude of an I(Kr)-like current when co-expressed with HERG. KCNE3 markedly changes KCNQ1 as well as HERG current properties. So far, KCNE2 (MirP1) has only been shown to modulate HERG current. Here we demonstrate the interaction of KCNE2 with the KCNQ1 subunit, which results in a drastic change of KCNQ1 current amplitude and gating properties. Furthermore, KCNE2 mutations also reveal their specific functional consequences on KCNQ1 currents. KCNQ1 and HERG appear to share unique interactions with KCNE1, 2 and 3 subunits. With the exception of KCNE3, mutations in all these partner subunits have been found to lead to an increased propensity for cardiac arrhythmias.

Animals↗
PubMed1998

Role of potassium channels in amyloid-induced cell death.

Basal forebrain cholinergic neurons are severely depleted early in Alzheimer's disease and appear particularly susceptible to amyloid beta-peptide (A beta) toxicity in vivo. To model this effect in vitro, a cholinergic septal cell line (SN56) was exposed to A beta. SN56 cells exhibited a tetraethylammonium (TEA)-sensitive outward K+ current with delayed rectifier characteristics. Increases of 64% (+/-19; p < 0.02) and 44% (+/-12; p < 0.02) in K+ current density were noted 6-12 and 12-18 h following the addition of A beta to SN56 cell cultures, respectively. Morphological observation and staining for cell viability showed that 25 +/- 4 and 39 +/- 4% of SN56 cells were dead after 48- and 96-h exposures to A beta, respectively. Perfusion of SN56 cells with 10-20 mM TEA blocked 71 +/- 6 to 92 +/- 2% of the outward currents, widened action potentials, elevated [Ca2+]i, and inhibited 89 +/- 14 and 68 +/- 14% of the A beta toxicity. High [K+]o, which depolarizes cell membranes and increases [Ca2+]i, also protected SN56 cells from A beta toxicity. This effect appeared specific since glucose deprivation of SN56 cells did not alter K+ current density and TEA did not protect these cells from hypoglycemic cell death. Furthermore, A beta was toxic to a dopaminergic cell line (MES23.5) that expressed a K+ current with delayed rectifier characteristics; K+ current density was not altered by A beta and MES23.5 cells were not protected by TEA from A beta toxicity. In contrast, a noncholinergic septal cell line (SN48) that shows minimal outward K+ currents was resistant to the toxicity of A beta. These data suggest that a K+ channel with delayed rectifier characteristics may play an important role in A beta-mediated toxicity for septal cholinergic cells.

Amyloid beta-Peptides↗
PubMed2001

Temperature-dependent expression of a squid Kv1 channel in Sf9 cells and functional comparison with the native delayed rectifier.

SqKv1A is a cDNA that encodes a Kv1 (Shaker-type) alpha-subunit expressed only in the giant axon and the parental giant fiber lobe (GFL) neurons of the squid stellate ganglion. We incorporated SqKv1A into a recombinant baculovirus for expression in the insect Sf9 cell line. Whole-cell patch-clamp recordings reveal that very few cells display functional potassium current (IK) if cultured at the standard postinfection temperature of 27 degrees C. At 18 degrees C, less SqKv1A protein is produced than at 27 degrees C, but cells with IK currents are much more numerous and can survive for at least 20 days postinfection (vs. approximately 5 days at 27 degrees C). Activation and deactivation kinetics of SqKv1A in Sf9 cells are slower (approximately 3- and 10-fold, respectively) than those of native channels in GFL neurons, but have similar voltage dependencies. The two cell types show only subtle differences in steady-state voltage-dependence of conductance and inactivation. Rates of IK inactivation in 20 mM external K are identical in the two cell types, but the sensitivity of inactivation to external tetraethylammonium (TEA) and K ions differ: inactivation of SqKv1A in Sf9 cells is slowed by external TEA and K ions, whereas inactivation of GFL IK is largely insensitive. Functional differences are discussed in terms of factors that may be specific to cell-type, including the presence of presently unidentified Kv1 subunits in GFL neurons that might form heteromultimers with SqKv1A.

Animals↗
PubMed1997

Electrical properties of periglomerular cells in the frog olfactory bulb.

Whole-cell patch clamp recording techniques were applied to periglomerular (PG) cells in slices of the frog olfactory bulb (OB) preparation to study the basic electrical properties of these inhibitory interneurons. The cells were intracellularly stained with Lucifer Yellow for precise identification. Under current-clamp conditions PG cells showed rich spontaneous excitatory synaptic activity at rest, usually leading to overshooting, TTX-sensitive action potentials. The passive cable properties of the cell membrane have been carefully characterised. Depolarisation of this neurone under voltage-clamp conditions activated a complex pattern of current flow, that has been dissected into its main components. The currents have been isolated resorting to their different kinetic and pharmacological properties. Four main voltage dependent ionic currents have been isolated, two inward currents, I(Na) and I(Ca), and two outward currents carried by potassium ions, one fast transient, I(A)-type and another similar to the delayed rectifier type. These currents have been characterised kinetically and pharmacologically. The functional implications of their properties are discussed.

Action Potentials↗
PubMed1991

Whole-cell clamp of dissociated photoreceptors from the eye of Lima scabra.

Voltage-dependent membrane currents were investigated in enzymatically dissociated photoreceptors of Lima scabra using the whole-cell clamp technique. Depolarizing steps to voltages more positive than -10 mV elicit a transient inward current followed by a delayed, sustained outward current. The outward current is insensitive to replacement of a large fraction of extracellular Cl- with the impermeant anion glucuronate. Superfusion with tetraethylammonium and 4-aminopyridine reversibly abolishes the outward current, and internal perfusion with cesium also suppresses it, indicating that it is mediated by potassium channels. Isolation of the inward current reveals a fast activation kinetics, the peak amplitude occurring as early as 4-5 ms after stimulus onset, and a relatively rapid, though incomplete inactivation. Within the range of voltages examined, spanning up to +90 mV, reversal was not observed. The inward current is not sensitive to tetrodotoxin at concentrations up to 10 microM, and survives replacement of extracellular Na with tetramethylammonium. On the other hand, it is completely eliminated by calcium removal from the perfusing solution, and it is partially blocked by submillimolar concentrations of cadmium, suggesting that it is entirely due to voltage-dependent calcium channels. Analysis of the kinetics and voltage dependence of the isolated calcium current indicates the presence of two components, possibly reflecting the existence of separate populations of channels. Barium and strontium can pass through these channels, though less easily than calcium. Both the activation and the inactivation become significantly more sluggish when these ions serve as the charge carrier. A large fraction of the outward current is activated by preceding calcium influx. Suppression of this calcium-dependent potassium current shows a small residual component resembling the delayed rectifier. In addition, a transient outward current sensitive to 4-aminopyridine (Ia) could also be identified. The relevance of such conductance mechanisms in the generation of the light response in Lima photoreceptors is discussed.

4-Aminopyridine↗
PubMed1985

Development of ionic channels during mouse neuronal differentiation.

Using a mouse embryonal teratocarcinoma (E.C.) cell line, it was possible to follow the sequence of development of ionic channels during neuronal differentiation, with patch-clamp techniques. 1003 E.C. cells were induced to differentiate into neurons by culturing them in defined medium without foetal calf serum (DARMON et al., 1981). Non-differentiated cells were not excitable and presented mainly 2 types of K+ channels: a Ca2+ activated K+ channel (220 pS in symmetrical K+) and a delayed rectifier (30 pS in symmetrical K+). When the cells start to grow neurites, a low threshold calcium current can be recorded, only if the cell is held at hyperpolarized potentials (-70 to -80 mV). Fully differentiated cells with long neurites presented a complete repertoire of ionic channels: voltage dependent Na+ and Ca2+ channels, Ca2+ activated K+ channel and K+ delayed rectifier.

Animals↗
PubMed1997

Identification of two nervous system-specific members of the erg potassium channel gene family.

Two new potassium channel genes, erg2 and erg3, that are expressed in the nervous system of the rat were identified. These two genes form a small gene family with the previously described erg1 (HERG) gene. The erg2 and erg3 genes are expressed exclusively in the nervous system, in marked contrast to erg1, which is expressed in both neural and non-neural tissues. All three genes are expressed in peripheral sympathetic ganglia. The erg3 channel produces a current that has a large transient component at positive potentials, whereas the other two channels are slowly activating delayed rectifiers. Expression of the erg1 gene in the sympathetic nervous system has potential implications for the etiology of the LQT2 form of the human genetic disease long QT syndrome.

Animals↗
PubMed1983

Slow components of potassium tail currents in rat skeletal muscle.

The kinetics of potassium tail currents have been studied in the omohyoid muscle of the rat using the three-microelectrode voltage-clamp technique. The currents were elicited by a two-pulse protocol in which a conditioning pulse to open channels was followed by a test step to varying levels. The tail currents reversed at a single well-defined potential (VK). At hyperpolarized test potentials (-100 mV and below), tail currents were inward and exhibited two clearly distinguishable phases of decay, a fast tail with a time constant of 2-3 ms and a slow tail with a time constant of approximately 150 ms. At depolarized potentials (-60 mV and above), tail currents were outward and did not show two such easily separable phases of decay, although a slow kinetic component was present. The slow kinetic phase of outward tail currents appeared to be functionally distinct from the slow inward tail since the channels responsible for the latter did not allow significant outward current. Substitution of Rb for extracellular K abolished current through the anomalous (inward-going) rectifier and at the same time eliminated the slow inward tail, which suggests that the slow inward tail current flows through anomalous rectifier channels. The amplitude of the slow inward tail was increased and VK was shifted in the depolarizing direction by longer conditioning pulses. The shift in VK implies that during outward currents potassium accumulates in a restricted extracellular space, and it is suggested that this excess K causes the slow inward tail by increasing the inward current through the anomalous rectifier. By this hypothesis, the tail current slowly decays as K diffuses from the restricted space. Consistent with such a hypothesis, the decay of the slow inward tail was not strongly affected by changing temperature. It is concluded that a single delayed K channel is present in the omohyoid. Substitution of Rb for K has little effect on the magnitude or time course of outward current tails, but reduces the magnitude and slows the decay of the fast component of inward tails. Both effects are consistent with a mechanism proposed for squid giant axon (Swenson and Armstrong, 1981): that (a) the delayed potassium channel cannot close while Rb is inside it, and (b) that Rb remains in the channel longer than K.

Animals↗
PubMed2001

Molecular cloning and expression of cERG, the ether à go-go-related gene from canine myocardium.

Given the anatomical and physiological similarities to the human heart, canine in vivo heart models may facilitate the analysis of molecular mechanisms underlying cardiac repolarization abnormalities. The development of such models depends, however, on information about canine K+ channels responsible for the establishment of IK currents. In this context, we isolated and sequenced the reverse transcript of the canine ether à go-go-related gene (cERG). The complementary deoxyribonucleic acid (cDNA-derived cERG polypeptide consists of 1,158 amino acids, the sequence of which shows striking homology to human, rat and mouse ERG subunits (97%, 94% and 95% identity respectively). In highly conserved peptide domains like the PAS domain, the membrane-spanning segments S1, S3-S6 and the pore-forming region, there was 100% identity. Analysis of cERG transcription revealed abundant expression of cERG messenger ribonucleic acid (mRNA) in heart and brain and low expression in liver, spleen and kidney. Membrane currents recorded in Xenopus oocytes expressing cERG channels showed functional properties very similar to the human K+ channel hERG, which encodes the alpha-subunit of the cardiac rapidly activating, delayed rectifier (IKr) channel.

Animals↗
PubMed2001

Testosterone-induced relaxation of rat aorta is androgen structure specific and involves K+ channel activation.

Recent studies have established that testosterone (Tes) produces acute (nongenomic) vasorelaxation. This study examined the structural specificity of Tes-induced vasorelaxation and the role of vascular smooth muscle (VSM) K+ channels in rat thoracic aorta. Aortic rings from male Sprague-Dawley rats with (Endo+) and without endothelium (Endo-) were prepared for isometric tension recording. In Endo- aortas precontracted with phenylephrine, 5-300 microM Tes produced dose-dependent relaxation from 10 microM (4 +/- 1%) to 300 microM (100 +/- 1%). In paired Endo+ and Endo- aortas, Tes-induced vasorelaxation was slightly but significantly greater in Endo+ aortas (at 5-150 microM Tes); sensitivity (EC(50)) of the aorta to Tes was reduced by nearly one-half in Endo- vessels. Based on the sensitivity (EC(50)) of Endo- aortas, Tes, the active metabolite 5alpha-dihydrotestosterone, the major excretory metabolites androsterone and etiocholanolone, the nonpolar esters Tes-enanthate and Tes-hemisuccinate (THS), and THS conjugates to BSA (THS-BSA) exhibited relative potencies for vasorelaxation dramatically different from androgen receptor-mediated effects observed in reproductive tissues, with a rank order of THS-BSA > Tes > androsterone = THS = etiocholanolone > dihydrotestosterone >> Tes-enanthate. Pretreatment of aortas with 5 mM 4-aminopyridine attenuated Tes-induced vasorelaxation by an average of 44 +/- 2% (25-300 microM Tes). In contrast, pretreatment of aortas with other K+ channel inhibitors had no effect. These data reveal that Tes-induced vasorelaxation is a structurally specific effect of the androgen molecule, which is enhanced in more polar analogs that have a lower permeability to the VSM cell membrane, and that the effect of Tes involves activation of K+ efflux through K+ channels in VSM, perhaps via the voltage-dependent (delayed-rectifier) K+ channel.

Androgens↗
PubMed1997

Mutations in the hminK gene cause long QT syndrome and suppress IKs function.

Ion-channel beta-subunits are ancillary proteins that co-assemble with alpha-subunits to modulate the gating kinetics and enhance stability of multimeric channel complexes. Despite their functional importance, dysfunction of potassium-channel beta-subunits has not been associated with disease. Recent physiological studies suggest that KCNE1 encodes beta-subunits (hminK) that co-assemble with KvLQT1 alpha-subunits to form the slowly activating delayed rectifier K+ (IKs) channel. Because KVLQT1 mutations cause arrhythmia susceptibility in the long QT syndrome (LQT), we hypothesized that mutations in KCNE1 also cause this disorder. Here, we define KCNE1 missense mutations in affected members of two LQT families. Both mutations (S74L, D76N) reduced IKs by shifting the voltage dependence of activation and accelerating channel deactivation. D76N hminK also had a strong dominant-negative effect. The functional consequences of these mutations would be delayed cardiac repolarization and an increased risk of arrhythmia. This is the first description of KCNE1 as an LQT gene and confirms that hminK is an integral protein of the IKs channel.

Amino Acid Sequence↗
PubMed2006

Molecular determinants of cocaine block of human ether-á-go-go-related gene potassium channels.

The use of cocaine causes cardiac arrhythmias and sudden death. Blockade of the cardiac potassium channel human ether-á-go-go-related gene (hERG) has been implicated as a mechanism for the proarrhythmic action of cocaine. hERG encodes the pore-forming subunits of the rapidly activating delayed rectifier K(+) channel (I(Kr)), which is important for cardiac repolarization. Blockade of I(Kr)/hERG represents a common mechanism for drug-induced long QT syndrome. The mechanisms for many common drugs to block the hERG channel are not well understood. We investigated the molecular determinants of hERG channels in cocaine-hERG interactions using site-targeted mutations and patch-clamp method. Wild-type and mutant hERG channels were heterologously expressed in human embryonic kidney 293 cells. We found that there was no correlation between inactivation gating and cocaine block of hERG channels. We also found that consistent with Thr-623, Tyr-652, and Phe-656 being critical for drug binding to hERG channels, mutations in these residues significantly reduced cocaine-induced block, and the hydrophobicity of the residues at position 656 dictated the cocaine sensitivity of the channel. Although the S620T mutation, which removed hERG inactivation, reduced cocaine block by 21-fold, the S620C mutation, which also completely removed hERG inactivation, did not affect the blocking potency of cocaine. Thus, Ser-620 is another pore helix residue whose mutation can interfere with cocaine binding independently of its effect on inactivation.

Binding, Competitive↗
PubMed2000

Mechanisms of I(Ks) suppression in LQT1 mutants.

Mutations in the cardiac potassium ion channel gene KCNQ1 (voltage-gated K(+) channel subtype KvLQT1) cause LQT1, the most common type of hereditary long Q-T syndrome. KvLQT1 mutations prolong Q-T by reducing the repolarizing cardiac current [slow delayed rectifier K(+) current (I(Ks) )], but, for reasons that are not well understood, the clinical phenotypes may vary considerably even for carriers of the same mutation, perhaps explaining the mode of inheritance. At present, only currents expressed by LQT1 mutants have been studied, and it is unknown whether abnormal subunits are transported to the cell surface. Here, we have examined for the first time trafficking of KvLQT1 mutations and correlated the results with the I(Ks) currents that were expressed. Two missense mutations, S225L and A300T, produced abnormal currents, and two others, Y281C and Y315C, produced no currents. However, all four KvLQT1 mutations were detected at the cell surface. S225L, Y281C, and Y315C produced dominant negative effects on wild-type I(Ks) current, whereas the mutant with the mildest dysfunction, A300T, did not. We examined trafficking of a severe insertion deletion mutant Delta544 and detected this protein at the cell surface as well. We compared the cellular and clinical phenotypes and found a poor correlation for the severely dysfunctional mutations.

Animals↗
PubMed1999

Phoneutria nigriventer toxin Tx3-1 blocks A-type K+ currents controlling Ca2+ oscillation frequency in GH3 cells.

GH3 cells present spontaneous Ca2+ action potentials and oscillations of intracellular Ca2+, which can be modified by altering the activity of K+ or Ca2+ channels. We took advantage of this spontaneous activity to screen for effects of a purified toxin (Tx3-1) from the venom of Phoneutria nigriventer on ion channels. We report that Tx3-1 increases the frequency of Ca2+ oscillations, as do two blockers of potassium channels, 4-aminopyridine and charybdotoxin. Whole-cell patch clamp experiments show that Tx3-1 reversibly inhibits the A-type K+ current (I(A)) but does not block other K+ currents (delayed-rectifying, inward-rectifying, and large-conductance Ca2+-sensitive) or Ca2+ channels (T and L type) in these cells. In addition, we describe the sequence of a full cDNA clone of Tx3-1, which shows that Tx3-1 has no homology to other known blockers of K+ channels and gives insights into the processing of this neurotoxin. We conclude that Tx3-1 is a selective inhibitor of I(A), which can be used to probe the role of this channel in the control of cellular function. Based on the effect of Tx3-1, we suggest that I(A) is an important determinant of the frequency of Ca2+ oscillations in unstimulated GH3 cells.

4-Aminopyridine↗
PubMed1994

Philanthotoxin inhibits Ca2+ currents in rat hippocampal CA1 neurons.

The wasp venom philanthotoxin-4.3.3 (PhTX-4.3.3) is an antagonist of glutamate transmission in the insect as well as in the mammalian brain. It was recently shown that PhTX-4.3.3 inhibits the N-methyl-D-aspartate (NMDA) transmission in rat hippocampus. In this study we show that dideaza-philanthotoxin-12 (dideaza-PhTX-12), an analogue of PhTX-4.3.3, is a potent antagonist of voltage-dependent Ca2+ currents in rat hippocampal CA1 neurons. At a concentration of 10 microM it reduces the Ca2+ current to 40%. Two voltage-dependent potassium currents, the A current and the delayed rectifier, were hardly affected by dideaza-PhTX-12, indicating selectivity of the drug for Ca2+ currents. As a consequence the philanthotoxins will inhibit the calcium influx via voltage dependent as well as NMDA mediaded calcium channels and thus reduce excitability in the hippocampus.

Animals↗