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  • 1
    Electronic Resource
    Electronic Resource
    Two types of modified cardiac Na+ channels after cytosolic interventions at the α-subunit capable of removing Na+ inactivation (1997)
    Springer
    European biophysics journal 25 (1997), S. 189-200 
    Details
    ISSN: 1432-1017
    Keywords: Key words Single cardiac Na+ channels ; Site-directed antipeptide antibody ; Proteolysis ; Protein reagents ; Calpain ; Stochastic mode switching
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract Failure of inactivation is the typical response of voltage-gated Na+ channels to the cytosolic presence of proteolytic enzymes, protein reagents such as N-bromoacetamide (NBA) or iodate, and antibodies directed against the linker between domains III and IV of the α-subunit. The present patch clamp experiments with cardiac Na+ channels aimed to test the hypothesis that these interventions may provoke the occurrence of non-inactivating Na+ channels with distinct kinetic properties. A site-directed polyclonal antibody (anti-SLP2, target sequence 1481–1496 of the cardiac Na+ channel α-subunit) eliminated fast Na+ inactivation to induce burst activity which was accompanied by the occurrence of two open states. A deactivation process terminated channel activity during membrane depolarization proceeding with time constants of close to 40 ms (at –40 mV). NBA-modified and iodate-modified Na+ channels were kinetically indistinguishable from the anti-SLP2-modified type since they likewise deactivate and, thus, attain an only moderate Po of close to 20%. This is fundamentally different from the behaviour of enzymatically-modified Na+ channels: after cytosolic proteolysis with α-chymotrypsin, trypsin or pronase, mean Po during membrane depolarization amounted to approximately 40% because deactivation operated extremely slowly and less efficiently (time constants 100–200 ms at –40 mV, as a minimum) or was virtually non-operating. In-vitro cleavage of the synthetic linker sequence 1481–1496 confirmed that this part of the α-subunit provides a substrate for these peptidases or reactants for NBA but cannot be chemically modified by iodate. This iodate resistance indicates that iodate-modified Na+ channels are based on a structural alteration of still another region which is also involved in Na+ inactivation, besides the linker between domains III and IV of the α-subunit. Endogenous peptidases such as calpain did not affect Na+ inactivation. This stresses the stochastic nature of a kinetic peculiarity of cardiac Na+ channels, mode-switching to a non-inactivating mode.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002490050031
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Thermodynamically specific gating kinetics of cardiac mammalian K (ATP) + channels in a physiological environment near 37°C (1995)
    Springer
    The journal of membrane biology 146 (1995), S. 85-90 
    Details
    ISSN: 1432-1424
    Keywords: K+ permeation ; Open state kinetics ; Q10 ; Arrhenius anomalies ; Temperature dependence ; cAMP-dependent phosphorylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Elementary K+ currents through isolated ATP-sensitive K+ channels from neonatal rat cardiocytes were recorded to study their temperature dependence between 9°C and 39°C. Elementary current size and, thus, K+ permeation through the open pore varied monotonically with temperature with a Q10 of 1.25 corresponding to a low activation energy of 3.9 kcal/mol. Open-state kinetics showed a complicated temperature dependence with Q10 values of up to 2.94. Arrhenius anomalies of τopen(1) and τopen(2) indicate the occurrence of thermallyinduced perturbations with a dominating influence on channel portions that are involved in gating but are obviously ineffective in altering pore-forming segments. At 39°C, open-state exit reactions were associated with the highest activation energy (O2 exit reaction: 12.1 kcal/ mol) and the largest amount of entropy. A transition from 19°C to 9°C elucidated a paradoxical kinetic response, shortening of both O-states, irrespective of the absence or presence of cAMP-dependent phosphorylation. Another member of the K+ channel family and also a constituent of neonatal rat cardiocyte membranes, 66 pS outwardly-rectifying channels, was found to react predictably since τopen increased on cooling. Obviously, cardiac K (ATP) + channels do not share this exceptional kinetic responsiveness to a temperature transition from 19°C to 9°C with other K+ channels and have a unique sensitivity to thermally-induced perturbations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232682
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Responsiveness of cardiac Na+ channels to antiarrhythmic drugs: The role of inactivation (1991)
    Springer
    The journal of membrane biology 122 (1991), S. 267-278 
    Details
    ISSN: 1432-1424
    Keywords: single cardiac Na+ channels ; open-state kinetics ; drug-induced blockade ; (-)-DPI
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary Elementary Na+ currents were recorded at 9°C in inside-out patches from cultured neonatal rat heart myocytes. In characterizing the sensitivity of cooled, slowly inactivating cardiac Na+ channels to several antiarrhythmic drugs including propafenone, lidocaine and quinidine, the study aimed to define the role of Na+ inactivation for open channel blockade. In concentrations (1–10 μmol/liter) effective to depressNP o significantly, propafenone completely failed to influence the open state of slowly inactivating Na+ channels. With 1 μmol/liter, τopen changed insignificantly to 96±7% of the control. Even a small number of ultralong openings of 6 msec or longer exceeding τopen of the whole ensemble several-fold and attaining τopen (at −45 mV) in cooled, (-)-DPI-modified, noninactivating Na+ channels proved to be drug resistant and could not be flicker-blocked by 10 μmol/liter propafenone. The same drug concentration induced in(-)-DPI-modified Na+ channels a discrete block with association and dissociation rate constants of 16.1 ± 5.3 × 106 mol−1 sec−1 and 675 ± 25 sec−1, respectively. Quinidine, known to have a considerable affinity for activated Na+ channels, in lower concentrations (5 μmol/liter) left τopen unchanged or reduced, in higher concentrations (10 μmol/liter) τopen only slightly to 81% of the predrug value whereasNP o declined to 30%, but repetitive blocking events during the conducting state could never be observed. Basically the same drug resistance of the open state was seen in cardiac Na+ channels whose open-state kinetics had been modulated by the cytoplasmic presence of F− ions. But in this case, propafenone reduced reopening and selectively abolished a long-lasting open state. This drug action is unlikely related to the inhibitory effect onNP o since hyperpolarization and the accompanying block attenuation did not restore the channel kinetics. It is concluded that cardiac Na+ channels cannot be flicker-blocked by antiarrhythmic drugs unless Na+ inactivation is removed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01871427
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    Paper (German National Licenses)
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