Pharmacology of Calcium Channels in Cardiac Muscle, Vascular Muscle, and Neurons
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The properties of voltage-dependent calcium channels in muscle cells and neurons have been studied using the whole-cell patch clamp technique. Cardiac muscle cells, vascular muscle cells, and neurons all have multiple types of calcium channels, and the different types have different pharmacological properties. The predominant calcium current in most cardiac and vascular muscle cells is carried through L-type calcium channels, which are potently and completely blocked by dihydropyridine drugs; the block is voltage-dependent, and is more potent at depolarized holding potentials where the calcium current is partly inactivated. In neurons, much less of the high-threshold calcium channel current is blocked by dihydropyridines, because much of it is carried through N-type calcium channels, which are not blocked by dihydropyridines but are blocked by the peptide toxin omega-conotoxin GVIA. In addition to L-type and N-type calcium channels, rat neurons have a third type of high-threshold calcium channel that is not blocked by either omega-conotoxin or dihydropyridines. Some neurons also have a fourth type of calcium current, a low threshold current carried by T-type calcium channels.Keywords:
P-type calcium channel
Cardiac muscle
N-type calcium channel
T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.
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Mibefradil
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Graphical Abstract Abstract figure legend HCN channels play an evolutionarily conserved pacemaker role in renal pelvic smooth muscle (RPSM) of lower and higher order mammals. The function of hyperpolarization-activated cation (HCN) channels in smooth muscle pacemakers remains controversial. Renal pelvic smooth muscle pacemakers trigger smooth muscle contractions that expel waste from the kidney, and HCN channels have been localized to these pacemaker tissues. To date, however, the mechanisms underlying RPSM pacemaker activity remain elusive. RPSM pacemaker activity was investigated in both lower (top left) and higher order (bottom left) mammalian models, which exhibit divergent upper urinary tract anatomies. We performed morphological and functional studies from the single-molecule to the whole-organ level and showed that HCN channels drive RPSM pacemaker activity. RPSM pacemakers (boxed regions) integrated into the muscular syncytium, expressed HCN channels on their plasmalemma and exhibited the Ih ‘funny’ pacemaker current conducted by HCN channels. Critically, HCN channel block abolished electrical pacemaker activity and peristaltic smooth muscle contractions in both lower and higher order mammalian upper urinary tracts. Thus, HCN channels play an evolutionarily conserved pacemaker role in RPSM pacemakers.
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1. Calcium channel activity was recorded in chromaffin cells in the cell‐attached condition, using 110 mM‐Ba2+ as the permeant ion. 2. One type of calcium channel had a conductance of 16 pS, was completely inactivated at a holding potential of ‐20 mV and was insensitive to dihydropyridine agonists and antagonists. These characteristics correspond to a calcium channel of the N‐type. 3. A second type of calcium channel was active at holding potentials of ‐30 mV and above, had a channel conductance of 31 pS, and was sensitive to the dihydropyridine agonist, Bay K 8644. The channel opened along two dominant modes with characteristic time constants of 0.5 and 5 ms. The main effect of Bay K 8644 was to increase the probability of both short and long openings with no change in their relative proportions (6 to 1 respectively). These characteristics correspond to a calcium channel of the L‐type. 4. omega‐Conotoxin affected the activity of both N‐ and L‐type channels. It drastically reduced the number of N‐type channel openings and produced complex changes in L‐type channel activity. Long openings were less frequent and the conductance during short openings was slightly smaller than that measured in the presence of Bay K 8644. 5. The discussion focuses on modulation of L‐type channel activity. Openings of L‐type channels are rarely recorded in the cell‐attached configuration under control conditions. Addition of Bay K 8644 is needed to reveal the presence of L‐type channels. By contrast, L‐type currents recorded in the whole‐cell configuration are always observed and are insensitive to Bay K 8644. These results indicate that L‐type channels are normally inoperable in chromaffin cells.
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The early studies of cardiac and smooth muscle cells provided evidence for two different calcium channels, the L-type (also called high-voltage activated [HVA]) and T-type (low-voltage activated [LVA]). These calcium channels provided calcium for muscle contractions and pace-making activities. As might be expected, the number of different calcium channels increased when researchers studied neurons and the identification of the neuronal calcium channels has proven to be much more difficult than with the muscle calcium channels. There are two reasons for this difficulty; (1) a larger number of different calcium channels in neurons and (2) many of the different calcium channels have similar kinetic properties. This review uses the N-type calcium channel to illustrate the difficulties in identifying and characterizing calcium channels in neurons. It shows that the discovery of toxins that can specifically block single calcium channel types has made it possible to easily and rapidly discern the physiological roles of the different calcium channels in the neuron, Without these toxins it is unlikely that progress would have been as rapid.
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At least four calcium channel subtypes (P, T, N, and L) have now been classified on the basis of their biophysical and/or pharmacological properties. L-type channels, a channel family particularly important to physiological function of the cardiovascular system, are identified by their slow voltage- and calcium-dependent inactivation as well as their sensitivity to dihydropyridine (DHP) calcium channel antagonists. In this study, we report the results of experiments in which we have measured the DHP modulation of recombinant calcium channel activity in cells transfected with alpha 1 subunits of cardiac and smooth muscle L-type calcium channels. We find subunit-dependent differences in the voltage and concentration dependence of channel modulation. Our results provide evidence for a molecular basis for DHP sensitivity of heart and smooth muscle calcium channels and, additionally, indicate that, even within one family of calcium channels, slight differences in channel structure can cause marked differences ...
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Abstract The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured using the fluorescent calcium chelator fura‐2. The types of calcium channels present at the synaptic terminal were determined by the inhibitory action of calcium channel blockers on potassium‐induced [ 3 H]GABA release in the same cell preparation. L‐, N‐, P‐, Q‐ and R‐/T‐type voltage dependent calcium channels were differentially distributed in somata, neurites and nerve terminals. ω‐conotoxin MVIIC (ω‐CgTx MVIIC) inhibited approximately 40% of the Ca 2+ ‐rise in both somata and neurites and 60% of the potassium induced [ 3 H]GABA release, indicating that the Q‐type channel is the quantitatively most important voltage dependent calcium channel in all parts of the neuron. After treatment with thapsigargin the increase in cytosolic calcium was halved, indicating that calcium release from thapsigargin sensitive intracellular calcium stores is an important component of the potassium induced rise in cytosolic calcium concentration. The results of this investigation demonstrate that pharmacologically distinct types of voltage dependent calcium channels are differentially localized in cell bodies, neurites and nerve terminals of mouse cortical neurons but that the Q‐type calcium channel appears to predominate in all compartments.
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At least four calcium channel subtypes (P, T, N, and L) have now been classified on the basis of their biophysical and/or pharmacological properties. L-type channels, a channel family particularly important to physiological function of the cardiovascular system, are identified by their slow voltage- and calcium-dependent inactivation as well as their sensitivity to dihydropyridine (DHP) calcium channel antagonists. In this study, we report the results of experiments in which we have measured the DHP modulation of recombinant calcium channel activity in cells transfected with alpha 1 subunits of cardiac and smooth muscle L-type calcium channels. We find subunit-dependent differences in the voltage and concentration dependence of channel modulation. Our results provide evidence for a molecular basis for DHP sensitivity of heart and smooth muscle calcium channels and, additionally, indicate that, even within one family of calcium channels, slight differences in channel structure can cause marked differences in channel pharmacology.
R-type calcium channel
N-type calcium channel
L-type calcium channel
Cardiac action potential
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