Biomedical Engineering Reference
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et al.
2010
). In neurons, VGCC are located at presynaptic terminals and are
responsible for fast neurotransmission (Cao et al.
2004
; Reid et al.
2004
) . Neuronal
VGCC also regulate synaptic plasticity during neuronal activity, particularly through
the activation of gene expression (Dolmetsch et al.
2001
). Finally, VGCC are able
to initiate hormone release in endocrine tissues and activate calcium-dependent
enzymes (Comunanza et al.
2010
). Voltage-gated calcium channels have been
classified based on their pharmacological and electrophysiological profiles: T-, N-,
L-, Q-, P-, and R-types (Catterall et al.
2005
). Each family of calcium channels is
associated with a unique physiological role. Two main types have been described,
the T-type or LVA (low voltage activated channels) and the HVA (high voltage acti-
vated) (Bean
1985
; Gardoni
2008
; Tsien et al.
1988,
1991
) . The T-type channels
activate at potentials more negative than −40 mV, exhibit a small unitary conduc-
tance, and inactivate rapidly upon opening. Because these channels activate close to
resting membrane potentials, they regulate cellular excitability. N-, L-, R-, Q-, and
P-type channels activate at more positive potentials and are therefore named high-
voltage activated. These channels show overlapping biophysical profiles, yet they
are distinguished by their pharmacological responses to both dihydropyridine ago-
nists and antagonists, as well as specific peptide inhibitors isolated from various
venoms (Doering and Zamponi
2005
) .
HVA calcium channels are heteromultimeric protein complexes which are formed
through association of multiple subunits (Cava 1, Cav a 2- d and Cavb). These sub-
units associate to make a functional HVA calcium channel complex whereas a single
pore-forming Cava1 subunit has been reported for LVA channels. The Cavα1 sub-
unit consists of four homologous domains (I through IV), flanked by N-terminal and
C-terminal regions. The four domains are linked through cytoplasmic regions and
each domain is comprised of six putative membrane spanning helices (termed
S1-S6) as well as a pore-lining region. The intracellular regions linking the four
domains of the calcium channel Cava1 subunit form interaction sites for regulatory
proteins, and are potential targets for second messenger regulation (calmodulin,
kinases, phosphatases, …) (Catterall
2000
; Catterall et al.
2005
) . The major func-
tional properties of the channel are shaped by the pore-forming a1 subunit which
defines the calcium channel subtype, whereas the other subunits modulate the prop-
erties of Cava1. Ten different calcium channel a1 subunits have been cloned and
functionally expressed. They are grouped into three major families: Cav1, Cav2 and
Cav3. The Cav3 family (Cav3.1 through Cav3.3) encodes T-type calcium channels
(Perez-Reyes
2003
) Cav2.1, Cav2.2 and Cav2.3, respectively, encode P/Q-type,
N-type and R-type channels, and the Cav1 family (Cav1.1 through Cav1.4) repre-
sents the family of L-type calcium channels (Catterall et al.
2005
) . Four distinct
genes (each with several splice variants) of ancillary Cavb subunits (Cavb 1 through
Cavb4), and four genes encoding Cava
2
- d subunits (Cava
2
- d1 through Cava
2
- d 4)
have been cloned. When coexpressed with the pore-forming Cava1 subunit, Cavb
and Cava
2
- d subunits are able to alter the biophysical properties of the channel,
voltage-dependences and rates of activation-inactivation, and increase the trafficking
of Cava1 subunit to the plasma membrane (Arikkath and Campbell
2003
; Bichet
et al.
2000
; Dolphin
2003a
; Yasuda et al.
2004
) . Furthermore, the Cav b is able to act
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