DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

A. Voltage-activated Na + channel
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Depolarization
Ion
flux
+
CHAPTER 3
Closed
B. Ligand-gated Na + channel
Hyperpolarization
ACh
γ δ
Open
Membrane depolarization
alters position of voltage sensors
Figure 3–9. Schematic diagram of two types of ion channels regulated by receptors and drugs. A. Diagram of a voltage-activated Na +
channel with the pore in the open and closed state. The P loops are shown in blue, angled into the pore to form the selectivity filter.
The S4 helices forming the voltage sensor are shown in orange, with the positively charged amino acids displayed as red dots.
B. Ligand-gated nicotinic acetylcholine receptor expressed in the skeletal muscle neuromuscular junction. The pore is made up of five
subunits, each with a large extracellular domain and four transmembrane helices (one of these subunits is shown at the left of panel B).
The helix that lines the pore is shown in blue. The receptor is composed of 2 α subunits, and β, γ, and δ subunits. See text for discussion
of other ligand-gated ion channels. Detailed descriptions of specific channels are given throughout the text in relation to the therapeutic
actions of drugs affecting these channels (see especially Chapters 11, 14 and 20). (Adapted with permission from Purves, D,
Augustine, GJ, Fitzpatrick, D, Hall, WC, LaMantia, AS, McNamara, JO, and White, LE (eds). Neuroscience, 4ed. Sinauer Associates,
Inc., 2008.)
α
γ δ
β
α
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION
Voltage-gated Ca 2+ channels have a similar architecture to
voltage-gated Na + channels with a large α subunit (four domains of
six membrane-spanning helices) and three regulatory subunits (the
β, δ and γ subunits). There are multliple isoforms of these channels
that are widely expressed in nerve, cardiac and smooth muscle cells.
Ca 2+ channels can be responsible for initiating an action potential (as
in the pacemaker cells of the heart), but are more commonly responsible
for modifying the shape and duration of an action potential initiated
by fast voltage-gated Na + channels (Purves and McNamara,
2008). These channels initiate the influx of Ca 2+ that stimulates the
release of neurotransmitters in the central, enteric, and autonomic
nervous systems, and that control heart rate and impulse conduction
in cardiac tissue (Chapters 8, 14, and 27). The L-type voltage-gated
Ca 2+ channels are subject to additional regulation via phosphorylation
by PKA. Thus, when the sympathetic nervous system releases norepinephrine
onto β adrenergic receptors in cardiac tissue, raising cAMP
and activating PKA, the phosphorylated L-type channels allow more
Ca 2+ to flow into the cytoplasm, increasing the force of contraction.
Voltage-gated Ca 2+ channels expressed in smooth muscle regulate
vascular tone; the intracelluar concentration of Ca 2+ is critical to regulating
the phosphorylation state of the contractile apparatus via the
activity of the Ca 2+ /calmodulin-sensitive myosin light chain kinase.
Accordingly, the Ca 2+ channel antagonists such as nifedipine, diltiazem,
and verapamil are effective vasodilators and are widely used to
treat angina, cardiac arrhythmias, and hypertension.
Voltage-gated K + channels are the most numerous and structurally
diverse members of the voltage-gated channel family.
Humans express ~78 distinct K + channels and nearly all of them are