The Voltage Sensor

Voltage-dependent channels, such as the classical sodium or potassium channels in nerve tissue, change their conductance with membrane potential. The changes in conductance are a very steep function of membrane voltage conductance values can increase as much as 150 times for an increment of 10 mV in membrane potential (Hodgkin and Huxley, 1952). 

The ion current through the channel is the result of flow through an open pore under the influence of the electrochemical gradient. Thus the effective conductance of the channel depends on the open channel conductance and the fractional time the channel spends in the open state, also called open probability (P0). By recording the currents through single channels it is possible to measure the voltage dependence of the 

The large voltage dependence of these voltage dependent channels dictate that a large amount of charge move in the membrane electric held. Typically, at negative (inside) membrane potential, the channel is mostly closed and at positive potentials is mostly open. Then, the open 

In Shaker the value of (7, ax is about 13 e per channel (Schoppa et at., 1992). In the skeletal muscle Na channel the value of OIIlilx was 12 e 

When the first voltage-dependent ion channel was cloned and sequenced, it was recognized that the fourth transmembrane segment had a string of basic amino acids organized as one every three residues 

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Ca2+ Channel Blockers. Figure 1 Most voltage-gated Ca2+ channels exist as a hetero-oligomeric complex of several subunits, a 1 subunits form the Ca2+-selective ion pore and contain the voltage-sensors of the channel. 

DICR (depolarization-induced Ca2+ release) is Ca2+ release triggered by depolarization of the sarcolemma. In skeletal muscle, conformational change in the voltage sensor (a 1S subunit of the dihydropyridine receptor) in the T-tubule is directly transmitted to the... 

Dihydropyridine receptor (DHPR) is a member of voltage-dqiendent Ca2+ channels (CaVi, L-type), which specifically binds to dihydropyridine derivatives, a group of the Ca2+ channel blockers. Cav 1.1 works as the voltage sensor for skeletal muscle contraction, and Cay 1.2, as Ca2+-influx channel for cardiac muscle contraction. 

HVA calcium channels are biochemically hetero-oligomeric complexes of five proteins encoded by four gene families (Fig. 1) The ax subunits of 190-250 kDa contain the voltage-sensor, the selectivity filter, the ion-conducting pore, the binding sites for most calcium... 

The voltage sensor is the part of a channel protein responsible for detection of the membrane potential. A voltage sensor of the voltage-dependent Na+ channel was predicted by Hodgkin and Huxley in 1952. Positively charged amino acid residues in S4 of each repeat play an essential role as the voltage sensor. 

According to Schneider and Chandler (1973), depolarization of the T-tubules affects sensors which open Ca " channels in the SR. The sensors are modified Ca channels which act as voltage sensors (Tanabe et al., 1987). The signal from the sensor reaches the SR and opens the Ca channels with the release of Ca to the myoplasm. The Ca channels in the SR system are opened by micromolar [Ca ], mM [ATP], and caffeine but are inhibited by Mg (Smith et al., 1986 Rosseau et al., 1988). The channels are closed in resting muscle and are opened when the voltage sensor is activated. 

Possible mechanisms responsible for the decreased Ca release are changes in the sensitivity of the voltage sensor in the T-tubular system or in the SR Ca channel to the sensor stimulus. A third possibility would be a decreased availability... 

Fig. 16.1 Sodium channel structure. Schematic representation of the sodium channel subunits, a, ySl and / 2. (A) The a-subunit consists of four homologous intracelIularly linked domains (I—IV) each consisting of six connected segments (1-6). The segment 4 of each of the domains acts as the voltage sensor, physically moving out in response to depolarization resulting in activation of the sodium channel. The channel is inactivated rapidly by the linker region between III and IV docking on to the acceptor site formed by the cytoplasmic ends of S5 and S6 of domain IV. The / -subunits have a common structure, with the / 1 non-covalently bound, and f 2 linked by disulfide bonds to the a-channel...

Structural models for voltage-dependent gating of ion channels must identify the voltage-sensors or gating charges (Fig. 6-5A) within the channel structure and suggest a plausible mechanism for transmembrane movement... 

Bezanilla, F. The voltage sensor in voltage dependent ion channels. Physiol. Rev. 80, 555-592, 2000. 

New structures published by the MacKinnon team in 2005 eliminated the need for the antibody attachment (Fabs) to achieve protein crystallization and show the voltage sensors in the expected more upright position. This research is described in the following paragraphs. 

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