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WIREs Membr Transp Signal

L‐type Ca 2+ channels in heart and brain

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L‐type calcium channels (Cav1) represent one of the three major classes (Cav1–3) of voltage‐gated calcium channels. They were identified as the target of clinically used calcium channel blockers (CCBs; so‐called calcium antagonists) and were the first class accessible to biochemical characterization. Four of the 10 known α1 subunits (Cav1.1–Cav1.4) form the pore of L‐type calcium channels (LTCCs) and contain the high‐affinity drug‐binding sites for dihydropyridines and other chemical classes of organic CCBs. In essentially all electrically excitable cells one or more of these LTCC isoforms is expressed, and therefore it is not surprising that many body functions including muscle, brain, endocrine, and sensory function depend on proper LTCC activity. Gene knockouts and inherited human diseases have allowed detailed insight into the physiological and pathophysiological role of these channels. Genome‐wide association studies and analysis of human genomes are currently providing even more hints that even small changes of channel expression or activity may be associated with disease, such as psychiatric disease or cardiac arrhythmias. Therefore, it is important to understand the structure–function relationship of LTCC isoforms, their differential contribution to physiological function, as well as their fine‐tuning by modulatory cellular processes. WIREs Membr Transp Signal 2014,3:15–38. doi: 10.1002/wmts.102

Conflict of interest: The authors have declared no conflicts of interest for this article.

Voltage‐gated Ca2+ channel (VGCC) complex. γ Subunits associate only with VGCC complexes in skeletal muscle and heart; drug‐binding domains for Ca2+‐channel blockers are located only on the α1 subunit; and their binding domains have been mapped.
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Schematic representation of the role of Cav1.2 and Cav1.3 L‐type calcium channels (LTCCs) in the persistent nucleus accumbens (NAc) molecular adaptations following extended withdrawal from repeated cocaine exposure. (a) The cocaine‐naive dopamine D1‐containing NAc neuron expresses AMPA receptors (GluA1/GluA2 tetramers) and Cav1.2 channels on the cell surface. (b) Twenty‐one days following withdrawal from repeated cocaine treatment increased phosphorylation of GluA1 at S845 in the NAc (a PKA site) was paralleled by an increase in cell surface GluA1 and GluA2 levels (and higher levels of Cav1.2 mRNA). (c) A cocaine challenge that elicits expression of cocaine psychomotor sensitization involves dopamine D1 receptors and Cav1.2‐activated CaMKII that increases GluA1 phosphorylation at S831 and Cav1.2‐activated ERK2, which further increases cell surface GluA1 over that seen in b. This long‐term adaptation is dependent on Cav1.3 channels and ERK2 in the ventral tegmental area (VTA) during the development of sensitization. (Reprinted with permission from Ref . Copyright 2011 Society for Neuroscience)
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Role of Cav1.3 channels for atrioventricular node (AVN) automaticity. Automaticity of wild‐type (WT) AVN cells (AVNCs) is dependent on both INa and ICa,L. (a and b) Application of 20‐μM tetrodotoxin (TTX) blocked action potential (AP) discharge. The membrane potential of AVNCs exposed to 20 μM TTX was stable at −59 ± 2 mV (n = 8). (c and d) Inhibition of ICa,L by 0.3 μM of the L‐type channel blocker isradipine in WT mouse AVNCs stopped pacemaker activity of AVNCs and the cell membrane potential depolarized to −35 ± 3 mV (n = 6). Only low‐amplitude oscillations of the membrane potential could be observed in isradipine‐treated AVNCs. These results indicated that pacemaking of mouse AVNCs required both INa and ICa,L for AP discharge. (e) Cav1.3−/− AVNCs display positive membrane potential and low‐amplitude oscillations without spontaneous APs very similar to isradipine‐blocked WT AVNCs. (f) Tonic hyperpolarizing current injection (black arrow) induced spontaneous AP firing in Cav1.3−/− AVNCs but with slower pacemaker activity and smaller AP amplitude. This suggests contribution of Cav1.3 channels to both diastolic depolarization as well as to the AP itself. The positive resting membrane potential in Cav1.3−/− AVNCs likely is due to the loss of crosstalk between Cav1.3 channels and SK2 K+ channels. In the intact AVN, Cav1.3−/− myocytes must be sufficiently hyperpolarized (e.g., by electrical coupling with the right atrium) to enable INa‐dependent APs and triggering by SAN impulses. (Reprinted with permission from Refs 103 and 104. Copyright 2011 Landes Bioscience)
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Cav1.3 splice variants have different biophysical properties. The C‐terminal modulator (CTM) controls Cav1.3 gating leading to altered biophysical properties in naturally occurring splice variants lacking the CTM. (a) Current activation properties shown in representative normalized I–V curves recorded in tsA‐201 cells expressing Cav1.3L (black), Cav1.343S (gray), and Cav1.342A (white) together with α2δ1 and β3 subunits; 2 mM Ca2+ was used as charge carrier. Half maximal activation voltage was significantly shifted by about 9 mV to more negative voltages and activation slope factor was significantly smaller. (b) Voltage dependence of inactivation elicited after 5‐second conditioning prepulses using 20‐millisecond test pulses to Vmax (no significant differences). (c) Percent ICa inactivation during 0.1‐, 0.25‐, 0.5‐, 1‐, and 5‐second test pulses to Vmax revealing significantly faster inactivation time course of short variants. (d) Voltage dependence of CDI: r250 corresponds to the fraction of ICa or IBa remaining after 250 milliseconds; f is the difference in r250 of IBa and ICa at −19 mV. Number of experiments is given in parentheses. Error bars reflect SEM, *P < 0.05, **P < 0.01, ***P < 0.001, one‐way ANOVA followed by Bonferroni post‐test. (Reprinted with permission from Ref . Copyright 2011 American Society for Biochemistry and Molecular Biology)
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Pore‐forming α1 subunits. Upper panel: Important functional domains discussed in this review are indicated. CaM, Ca2+‐calmodulin (blue circles indicate EF‐hands); IQ, PreIQ, and EF, CaM interaction domains in C‐terminus; NSCaTE, CaM interaction domains in N‐terminus (for N‐lobe of CaM, Cav1.3 only); PDZ, PDZ‐binding domain; DCRD and PCRD form the C‐terminal modulatory domain (CTM); AKAP, A‐kinase‐anchoring protein interaction site; cAMP‐PK and CaMKII, phosphorylation sites for kinases (Cav1.2: red dots; Cav1.3: blue dots); , proteolytic cleavage site in Cav1.1 and Cav1.2 α1; (sinoatrial node dysfunction and deafness) SANDD, in‐frame glycine insertion in SANDD patients. Lower panel: Cartoon of voltage sensing and pore domains of Cav α1 subunits; only two domains (half of the channel) are shown for clarity. Movements of the positively charged S4 helices (which serve as voltage sensors) in response to membrane potential changes are transmitted to the pore domain through the cytoplasmic S4–S5 linkers. S4 movement within the membrane is guided by interactions with negative charges provided by the S1–S3 helices.
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