Calcium Ion Channels and Their Blockers - Ion Channels and Their Inhibitors - page 267

calcium channels, called T-type, encoded by three distinct 1 subunit proteins

(Cav3.1-Cav3.3). The N, P, Q, and R type channels have all been shown to play
key roles in neurotransmitter release [ 8 - 10 ]. N-Type calcium channels are located
at presynaptic terminals throughout neurons and directly mediate spinal transmis-
sion of pain signals from the peripheral to the central nervous system. L -type
Ca 2 þ ion channels (LCCs) mediate muscle contraction, hormone secretion and
transcriptional events supporting learning and memory. Different subclasses of
L -channels exist, which may contribute to tissue selectivity. T-type calcium
channels are known to be implicated in pathogenesis of epilepsy and neuropathic
pain [ 11 , 12 ]. Unlike other types of calcium channels, T-type calcium channels
comprise only a pore-forming a1 subunit that is different from the calcium channel
subtypes [ 13 , 14 ]. Three different genes encode the a1 subunit of T-type calcium
channels, termed a1G, a1H, and a1I, respectively, each with its own distinct
functional and pharmacological profile [ 15 , 16 ].
Calcium ions are required for contraction of skeletal muscle and heart, release
of neurotransmitters and hormones, induction of cell death, activation of various
protein kinases and signaling cascades [ 17 ] for the cell cycle regulation [ 8 , 18 - 21 ]
and cellular proliferation and for the activation of early genes, which leads the cell
into G1 phase. In contrast, Ca 2 þ ion channels in inflammatory cells, such as
lymphocytes, mast cells, and neutrophils, are activated regardless of their mem-
brane potential [ 22 ] and are known as store operated calcium ion channels. They
have been shown to play important roles in the pathogenesis and exacerbation of
inflammatory and autoimmune diseases [ 23 - 26 ].
Depletion of intracellular calcium arrests the cell cycle in the G0/G1 and S
interphases [ 27 ], whereas regulation of the changes in intracellular calcium has
been proposed to be through a T-type calcium channel [ 28 ]. This is considered to be
important to control the cell cycle signaling pathway and to manage certain
pathophysiological diseases, where the cell cycle is aberrant.

a

2 Calcium Ion Channel Blockers

2.1 Mechanism of Action

The calcium ion channel blocking agents are a chemically, pharmacologically and
therapeutically heterogeneous group of drugs. L -type Ca 2 þ channels are sensitive to
numerous agonist and antagonist drugs that modulate the Ca 2 þ flow. The interac-
tion of an ion channel blocker with its receptor sites depends on whether the channel
is in a resting (closed), open (activated), or inactivated (closed) conformational
state. Calcium channel blockers work by blocking voltage-gated calcium channels
in cardiac muscle and blood vessels. The mechanism underlying the clinically
important use of calcium channel blockers is thought to be mediated by L -class
(“slow channels”) of voltage-gated calcium ions channels, which are abundant in