Calcium current

Another major second messenger in cells is calcium ion. Virtually any mammalian cell line can be used to measure transient calcium currents in fluorescence assays when cells are preloaded with an indicator dye that allows monitoring of changes in cytosolic calcium concentration. These responses can be observed in real time, but a characteristic of these responses is that they are transient. This may lead to problems with hemi-equilibria in antagonist studies whereby the maximal responses to agonists may be depressed in the presence of antagonists. These effects are discussed more fully in Chapter 6. 

The LVA ai subunits are blocked by moderate to low (10 pM) concentrations of nickel and bind the channel blocker mibefradil and kurotoxin. Both compounds are not specific LVA channel blockers because they block also Cavl. x and Cav2.x channels at about tenfold higher concentration. Interestingly, the endogenous cannabinoid anandamide binds to LVA channels and stabilises the inactivated state. This effect decreases T-type calcium current and neuronal firing activities. 

Oberlin E, Amara A, Bachelerie F et al (1996) The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382 833-835 Oh SB, Endoh T, Simen AA, Ren D, Miller RJ (2002) Regulation of calcium currents by chemok-ines and their receptors. J Neuroimmunol 123 66-75 Oh SB, Tran PB, GiUard SE, Hurley RW, Hammond DL, Miller RJ (2001) Chemokines and glycoprotein 120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 21 5027-5035... 

Takahashi, T, Kajikawa, Y and Tsujimoto, T (1998) G-Protein-coupled modulation of pres5maptic calcium currents and transmitter release by a GABAg receptor. J. Neurosci. 18 3138-3146. 

Thus the neurotransmitter role of ATP is well established in the periphary and also in sensory systems but its importance in the CNS remains to be elucidated (see Burnstock 1996). That requires the development of more specific antagonists and methods of mapping its location. The strong linkage of its P2x receptors to calcium currents may also provide a role for ATP in more long-term effects such as plasticity and neuronal development and death. 

Mackie K, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N-18 neuroblastoma cells. Mol Pharmacol 1993 44 498-503. 

FIGURE 7.15 Time-course of the increases in amplitude of the calcium current recorded from bullfrog atrial trabeculae following (A) rapid application of the p-adrenoceptor agonist isoprenaline (3 pM), and (B) rapid intracellular release of cAMP by flash-photolysis of o-nitrobenzyl cAMP. Applications/flashes were made at time zero. (From Nargeot et al., Proc. Natl. Acad. Sci. USA, 80, 2395-2399, 1983. With permission.)... 

Verapamil (Class IV antiarrhythmic drug) is an effective agent for atrial or supraventricular tachycardia. A Ca++ channel blocker, it is most potent in tissues where the action potentials depend on calcium currents, including slow-response tissues such as the SA node and the AV node. The effects of verapamil include a decrease in heart rate and in conduction velocity of the electrical impulse through the AV node. The resulting increase in duration of the AV nodal delay, which is illustrated by a lengthening of the PR segment in the ECG, reduces the number of impulses permitted to penetrate to the ventricles to cause contraction. 

Taussig R, Sanchez S, Rifo M, Gilman AG, Delardetti F. Inhibition of the omega conotoxin-sensitive calcium current by distinct G proteins. Neuron 1992 8 799-809. 

Takahashi, T., Forsythe, I. D., Tsujimoto, T., Barnes-Davies, M. and Onodera, K. Presynaptic calcium current modulation by a metabotropic glutamate receptor. Science 274 594-597,1996. 

Channels associated with capacitative calcium ion entry have been characterized electrophysiologically. In leukocytes, the current associated with the depletion of intracellular Ca2+ stores is highly Ca2+-selective and, on the basis of noise analysis, is believed to involve minute single channels [16] (see Ch. 6). This is the calcium release-activated calcium current (ICrac)- In other cell types, currents with significantly different properties have been identified, including in some instances store-operated nonse-lective cation channels. These marked electrophysiological distinctions may be indicative of distinct channel types mediating capacitative calcium ion entry in different cell types. 

Other antiseizure drugs regulate a subset of voltage-gated calcium currents 634... 

Other antiseizure drugs regulate a subset of voltagegated calcium currents. In contrast to partial seizures, which arise from localized regions of the cerebral cortex, the absence or petit mal form of generalized-onset seizures arise from the reciprocal firing of the thalamus and... 

Kelly, K. M., Gross, R. A and Macdonald, R. L. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci. Lett. 116 233-238,1990. 

Sartor P, Vacher P, Mollard P, Dufy B (1988) Tamoxifen reduces calcium currents in a clonal pituitary cell line. Endocrinology 123 534-540... 

Zweifach A, Lewis RS 1995 Rapid inactivation of depletion-activated calcium current (7CRAC) due to local calcium feedback. J Gen Physiol 105 209—226... 

Nabauer M, Callewaert G, Cleemann L, Morad M 1989 Regulation of calcium release is gated by calcium current, not gating charge, in cardiac myocytes. Science 244 800—803... 

Barrett, E. F., and Barrett, J. N. (1976) Separation of two voltage-sensitive potassium currents, and demonstration ofatetrodotoxin-resistance calcium current in frog motoneurons. J. Physiol., 255 737-774. 

Kuryshev, Y.A., Wang, L., Wible, B.A., Wan, X. and Ficker, E. (2006) Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents. Molecular Pharmacology, 69, 1216-1225. 

Banyasz, T., Fulop, L., Magyar, J., Szentandrassy, N., Varro, A., and Nanasi, P.P, Endocardial versus epicardial differences in L-type calcium current in canine ventricular myocytes studied by action potential voltage clamp, Cardiovasc. Res., 58, 66-75, 2003. 

A benzopyran derivative, RP-58866 (70) is under development by Rhone-Poulenc. Patch clamp studies in guinea-pig ventricular myocytes indicate that RP-58866 inhibits the inward rectifying potassium current (7ki) with no effects on the delayed rectifier, ATP-sensitive potassium currents or calcium currents [200]. RP-58866 increases APD90 of Purkinje fibres by about 45% at 0.3 yuM without affecting K ax [201]. The compound was effective... 

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