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Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of voltage-gated L-type calcium channels by organic calcium channel blockers is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac ischemia. Since decades these antihypertensives (such as the dihydropyridines amlodipine, felodipine or nifedipine) belong to the most widely prescribed drugs 
world-wide. Their tolerability is excellent because at therapeutic doses their pharmacological effects in humans are limited to the cardiovascular system. During the last years substantial progress has been made to reveal the physiological role of different L-type calcium channel isoforms in many other tissues, including the brain, endocrine and sensory cells. 
Moreover, there is accumulating evidence about their involvement in various human diseases, such as Parkinson's disease, neuropsychiatric disorders and hyperaldosteronism. In this review we discuss the pathogenetic role of L-type calcium channels, potential new indications for existing or isoform-selective compounds and strategies to minimize potential side effects.

No MeSH data available.


Related in: MedlinePlus

Distinct biophysical and pharmacological properties of Cav1.2 and Cav1.3. a, When heterologously expressed in tsA-201 cells Cav1.3L channels (L designating the C-terminally long splice variant) activate at lower voltages (and with a steeper voltage-dependence) than Cav1.2. This lower activation range has been confirmed for native LTCCs in tissues allowing separation of Cav1.3 and Cav1.2 current components (sinoatrial node and adrenal chromaffin cells [74, 80],). Classical low-voltage activated T-type Ca2+ channels (shown for Cav3.1) activate more negative than Cav1.3. The half-maximal activation voltages strongly depend on the concentration and nature of the extracellular charge carrier and the intracellular cations replacing potassium (for details see [116]). In panel a recordings were made with 15 mM extracellular Ca2+ as charge carrier. Current-voltage relationships are parallel-shifted by about 15 mV to more negative voltages [11, 87] at physiological (2 mM) extracellular Ca2+ concentrations, placing Cav1.3 activation in a voltage-range allowing subthreshold inward current in many cells. Notice that C-terminally short Cav1.3 splice variants activate at about 7 mV more negative voltages than Cav1.3L [116] (not illustrated). b, Concentration-response relationship of inhibition of Cav1.3 (long splice variant) and Cav1.2 by isradipine determined during 10-ms depolarizations to positive voltages from holding membrane potentials of -90 mV (filled circles) and -50 mV (open circles). Notice the strong voltage-dependence of Cav1.3 inhibition. Similarly, isradipine inhibits Cav1.2 at even lower concentrations at -50 mV holding potential (not shown). Taken from [10] and [116] with modifications.
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Figure 1: Distinct biophysical and pharmacological properties of Cav1.2 and Cav1.3. a, When heterologously expressed in tsA-201 cells Cav1.3L channels (L designating the C-terminally long splice variant) activate at lower voltages (and with a steeper voltage-dependence) than Cav1.2. This lower activation range has been confirmed for native LTCCs in tissues allowing separation of Cav1.3 and Cav1.2 current components (sinoatrial node and adrenal chromaffin cells [74, 80],). Classical low-voltage activated T-type Ca2+ channels (shown for Cav3.1) activate more negative than Cav1.3. The half-maximal activation voltages strongly depend on the concentration and nature of the extracellular charge carrier and the intracellular cations replacing potassium (for details see [116]). In panel a recordings were made with 15 mM extracellular Ca2+ as charge carrier. Current-voltage relationships are parallel-shifted by about 15 mV to more negative voltages [11, 87] at physiological (2 mM) extracellular Ca2+ concentrations, placing Cav1.3 activation in a voltage-range allowing subthreshold inward current in many cells. Notice that C-terminally short Cav1.3 splice variants activate at about 7 mV more negative voltages than Cav1.3L [116] (not illustrated). b, Concentration-response relationship of inhibition of Cav1.3 (long splice variant) and Cav1.2 by isradipine determined during 10-ms depolarizations to positive voltages from holding membrane potentials of -90 mV (filled circles) and -50 mV (open circles). Notice the strong voltage-dependence of Cav1.3 inhibition. Similarly, isradipine inhibits Cav1.2 at even lower concentrations at -50 mV holding potential (not shown). Taken from [10] and [116] with modifications.

Mentions: The voltage-sensitive, Ca2+-selective pores of all voltage-gated Ca2+ channels are comprised by α1-subunits which form hetero-oligomeric complexes with modulatory accessory subunits (different β- and α2δ-subunit isoforms [1];). Ten α1-subunit isoforms are encoded by separate genes with distinct pharmacological and biophysical properties and with different tissue expression and subcellular distribution [1, 2]. Detailed reviews about the structure, function and modulation of LTCCs have been published recently [2-6]. The Cav1 family (Cav1.1-Cav1.4) of α1-subunits form the L-type Ca2+ channel family. They are all sensitive to the main chemical classes of Ca2+-channel blockers (CCBs; dihydropyridines (DHPs), phenylalkylamines, benzothiazepines) but differ with respect to tissue expression and gating characteristics [1, 2]. Cav1.1 channels are almost exclusively found in skeletal muscle where they trigger depolarization-induced Ca2+ release from ryanodine receptors of the sarcoplasmic reticulum [7]. Cav1.4 channel expression is largely restricted to the retina [8, 9]. In contrast, Cav1.2 and Cav1.3 are expressed in many tissues and are even present together in the same cells. However, they differ in their gating properties and protein interactions which allows them to serve different physiological functions. A major distinguishing feature is the 9-15 mV more negative activation range of Cav1.3 channels [10, 11] (Fig. 1a). This permits them to open at threshold potentials in sinoatrial node (SAN) cells and neurons and to contribute to pacemaking and stabilization of plateau potentials [2, 12-14]. They also differ with respect to their modulation by C-terminal alternative splicing (for review see [2]).


Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?
Distinct biophysical and pharmacological properties of Cav1.2 and Cav1.3. a, When heterologously expressed in tsA-201 cells Cav1.3L channels (L designating the C-terminally long splice variant) activate at lower voltages (and with a steeper voltage-dependence) than Cav1.2. This lower activation range has been confirmed for native LTCCs in tissues allowing separation of Cav1.3 and Cav1.2 current components (sinoatrial node and adrenal chromaffin cells [74, 80],). Classical low-voltage activated T-type Ca2+ channels (shown for Cav3.1) activate more negative than Cav1.3. The half-maximal activation voltages strongly depend on the concentration and nature of the extracellular charge carrier and the intracellular cations replacing potassium (for details see [116]). In panel a recordings were made with 15 mM extracellular Ca2+ as charge carrier. Current-voltage relationships are parallel-shifted by about 15 mV to more negative voltages [11, 87] at physiological (2 mM) extracellular Ca2+ concentrations, placing Cav1.3 activation in a voltage-range allowing subthreshold inward current in many cells. Notice that C-terminally short Cav1.3 splice variants activate at about 7 mV more negative voltages than Cav1.3L [116] (not illustrated). b, Concentration-response relationship of inhibition of Cav1.3 (long splice variant) and Cav1.2 by isradipine determined during 10-ms depolarizations to positive voltages from holding membrane potentials of -90 mV (filled circles) and -50 mV (open circles). Notice the strong voltage-dependence of Cav1.3 inhibition. Similarly, isradipine inhibits Cav1.2 at even lower concentrations at -50 mV holding potential (not shown). Taken from [10] and [116] with modifications.
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Related In: Results  -  Collection

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Figure 1: Distinct biophysical and pharmacological properties of Cav1.2 and Cav1.3. a, When heterologously expressed in tsA-201 cells Cav1.3L channels (L designating the C-terminally long splice variant) activate at lower voltages (and with a steeper voltage-dependence) than Cav1.2. This lower activation range has been confirmed for native LTCCs in tissues allowing separation of Cav1.3 and Cav1.2 current components (sinoatrial node and adrenal chromaffin cells [74, 80],). Classical low-voltage activated T-type Ca2+ channels (shown for Cav3.1) activate more negative than Cav1.3. The half-maximal activation voltages strongly depend on the concentration and nature of the extracellular charge carrier and the intracellular cations replacing potassium (for details see [116]). In panel a recordings were made with 15 mM extracellular Ca2+ as charge carrier. Current-voltage relationships are parallel-shifted by about 15 mV to more negative voltages [11, 87] at physiological (2 mM) extracellular Ca2+ concentrations, placing Cav1.3 activation in a voltage-range allowing subthreshold inward current in many cells. Notice that C-terminally short Cav1.3 splice variants activate at about 7 mV more negative voltages than Cav1.3L [116] (not illustrated). b, Concentration-response relationship of inhibition of Cav1.3 (long splice variant) and Cav1.2 by isradipine determined during 10-ms depolarizations to positive voltages from holding membrane potentials of -90 mV (filled circles) and -50 mV (open circles). Notice the strong voltage-dependence of Cav1.3 inhibition. Similarly, isradipine inhibits Cav1.2 at even lower concentrations at -50 mV holding potential (not shown). Taken from [10] and [116] with modifications.
Mentions: The voltage-sensitive, Ca2+-selective pores of all voltage-gated Ca2+ channels are comprised by α1-subunits which form hetero-oligomeric complexes with modulatory accessory subunits (different β- and α2δ-subunit isoforms [1];). Ten α1-subunit isoforms are encoded by separate genes with distinct pharmacological and biophysical properties and with different tissue expression and subcellular distribution [1, 2]. Detailed reviews about the structure, function and modulation of LTCCs have been published recently [2-6]. The Cav1 family (Cav1.1-Cav1.4) of α1-subunits form the L-type Ca2+ channel family. They are all sensitive to the main chemical classes of Ca2+-channel blockers (CCBs; dihydropyridines (DHPs), phenylalkylamines, benzothiazepines) but differ with respect to tissue expression and gating characteristics [1, 2]. Cav1.1 channels are almost exclusively found in skeletal muscle where they trigger depolarization-induced Ca2+ release from ryanodine receptors of the sarcoplasmic reticulum [7]. Cav1.4 channel expression is largely restricted to the retina [8, 9]. In contrast, Cav1.2 and Cav1.3 are expressed in many tissues and are even present together in the same cells. However, they differ in their gating properties and protein interactions which allows them to serve different physiological functions. A major distinguishing feature is the 9-15 mV more negative activation range of Cav1.3 channels [10, 11] (Fig. 1a). This permits them to open at threshold potentials in sinoatrial node (SAN) cells and neurons and to contribute to pacemaking and stabilization of plateau potentials [2, 12-14]. They also differ with respect to their modulation by C-terminal alternative splicing (for review see [2]).

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of voltage-gated L-type calcium channels by organic calcium channel blockers is a well-established pharmacodynamic concept for the treatment of hypertension and cardiac ischemia. Since decades these antihypertensives (such as the dihydropyridines amlodipine, felodipine or nifedipine) belong to the most widely prescribed drugs 
world-wide. Their tolerability is excellent because at therapeutic doses their pharmacological effects in humans are limited to the cardiovascular system. During the last years substantial progress has been made to reveal the physiological role of different L-type calcium channel isoforms in many other tissues, including the brain, endocrine and sensory cells. 
Moreover, there is accumulating evidence about their involvement in various human diseases, such as Parkinson's disease, neuropsychiatric disorders and hyperaldosteronism. In this review we discuss the pathogenetic role of L-type calcium channels, potential new indications for existing or isoform-selective compounds and strategies to minimize potential side effects.

No MeSH data available.


Related in: MedlinePlus