Voltage-gated Ca + channels

Autoantibodies are directed against nicotinic acetylcholine receptors in myasthenia gravis, resulting in receptor loss, skeletal muscle paralysis, and dysfunction (100). In addition, antibodies directed against voltage-gated Ca " channels produce similar neuromuscular dysfunction of Lambert-Eaton... 

Figure 5.1 Mechanism of action at a chemical synapse. The arrival of an action potential at the axon terminal causes voltage-gated Ca++ channels to open. The resulting increase in concentration of Ca++ ions in the intracellular fluid facilitates exocytosis of the neurotransmitter into the synaptic cleft. Binding of the neurotransmitter to its specific receptor on the postsynaptic neuron alters the permeability of the membrane to one or more ions, thus causing a change in the membrane potential and generation of a graded potential in this neuron.

Pregabalin binds to the subunit of the voltage-gated Ca channel, resulting in a decrease in the release of several excitatory neurotransmitters. 

The decisive element in exocytosis is the interaction between proteins known as SNAREs that are located on the vesicular membrane (v-SNAREs) and on the plasma membrane (t-SNAREs). In the resting state (1), the v-SNARE synaptobrevin is blocked by the vesicular protein synaptotagmin. When an action potential reaches the presynaptic membrane, voltage-gated Ca "" channels open (see p. 348). Ca "" flows in and triggers the machinery by conformational changes in proteins. Contact takes place between synaptobrevin and the t-SNARE synaptotaxin (2). Additional proteins known as SNAPs bind to the SNARE complex and allow fusion between the vesicle and the plasma membrane (3). The process is supported by the hydrolysis of GTP by the auxiliary protein Rab. 

The available Ca channel blockers exert their effects primarily at voltage-gated Ca channels of the plasma membrane. There are at least several types of channels—L, T, N, P/Q and R—distinguished by their electrophysiological and pharmacological characteristics. The blockers act at the L-type channel at three distinct receptor sites (Fig. 19.2). These different receptor interactions underlie, in part, the qualitative and quantitative differences exhibited by the three principal classes of channel blockers. 

The open state of the Ca channels of the cell membrane is controlled by different signals. We know of voltage-gated Ca channels that are opened by a depolarization or change in membrane potential. There are also Ca chaimels that are controlled by G-protein-mediated signal transmission pathways, and ligand-gated channels (see Chapter 16). It is also reported that InsPs can activate Ca " channels in the cell membrane. 

In the presynaptic cell, the neurotransmitters are stored in vesicles. On arrival of an electrical signal (action potential, see 16.2), an influx of Ca takes place into the presynaptic cell as voltage-gated Ca channels are opened. The increase in Ca concentration leads to fusion of the vesicles with the membrane of the postsynaptic cell. The neurotransmitters are released into the synaptic cleft and diffuse to a corresponding receptor on the surface of the postsynaptic cell. Binding of the nemotransmitter to the receptor induces opening of an ion channel that is a component of the receptor. The type of ions that can enter depends on the selectivity of the ion channel. There are Na K, Ca and Cf specific ion channels. The ion flux creates an electric signal in the post-... 

Many proteins contribute centrally to the delicate balance of Ca in cardiac myocytes that controls cardiac contractility and influence electrical activity. These include voltage-gated Ca channels, RyR, SERCA2, PLN, calsequestrin and regulatory... 

Arrival of an action potential at the synaptic knoh opens voltage-gated Ca + channels in the plasma membrane. 

Figure 5.12. Regulation of insulin secretion by glucose in the pancreatic islet p-cell. An increase in glucose will yield increased ATP levels, which in turn will close the Kj. channels and partially depolarize the membrane. Opening of voltage-gated Ca channels will trigger exocytosis of insulin.

In striated muscle, the sheer amount of filaments is such that we actually need quite a bit of calcium to swiftly saturate the troponin molecules and trigger contraction. The lion s share of this calcium is not obtained from the extracellular space (viathe voltage-gated Ca channel, the dihydropyridine receptor - see later) but from the intracellular storage, more specifically from the endoplasmic reticulum, which somebody found necessary to christen sarcoplasmic reticulum in the muscle cell (gr. sarx, sarkos = flesh). It is released from there by a specialized Ca channel, the ryanodine receptor (RyR). This channel is activated by cytosolic calcium, which of course creates a fast and powerful... 

Figure 7.3. Mechanism of transmitter release, a Thepresynap-tic action potential opens voltage-gated Ca channels. Ca triggers exocytosis of neurotransmitters stored in piesynaptic vesicles. b Some proteins (out of mat r more) that are involved in exocytosis. Ca is involved at multiple stages. By binding to calmodulin (CaM), it promotes phosphorylation of synapsin, which primes the transmitter vesicle but does not immediately lead to exocytosis. Adhesion of primed vesicles to the presynap-tic membrane is mediated by synaptobrevin and other SNARE proteins. Synaptotagmin is activated directly by Ca and participates in the final step of secretiom...

Catterall WA. Structure and regulation of voltage-gated Ca channels. Annu. Rev. Cell Dev. Biol. 2000 16 521-555. 

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