Limits...
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

Human Cav1.3 mutations associated with ASD and PASNA. The transmembrane domain structure of Cav1.3 α1-subunit is illustrated. α1-subunits of voltage gated Ca2+ channels consist of four homologous repeats (I-IV), each comprising six transmembrane segments. Segments 1-4 of each domain form the voltage-sensor whereas segments 5 and 6 build the pore and activation gates. ASD-associated Cav1.3 mutations are highlighted in orange [68, 69, 117], PASNA-linked mutations shown in blue [70]. A59V, S1977L, and R2021H have not yet been analyzed functionally.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5384371&req=5

Figure 2: Human Cav1.3 mutations associated with ASD and PASNA. The transmembrane domain structure of Cav1.3 α1-subunit is illustrated. α1-subunits of voltage gated Ca2+ channels consist of four homologous repeats (I-IV), each comprising six transmembrane segments. Segments 1-4 of each domain form the voltage-sensor whereas segments 5 and 6 build the pore and activation gates. ASD-associated Cav1.3 mutations are highlighted in orange [68, 69, 117], PASNA-linked mutations shown in blue [70]. A59V, S1977L, and R2021H have not yet been analyzed functionally.

Mentions: In addition to PD, inhibition of pathologically increased Cav1.3 activity may also be of therapeutic benefit in other brain disorders. We have recently reported that two de novo mutations in the CACNA1D gene (Cav1.3 α1-subunit) identified in humans with ASD cause a pronounced gain-of-channel-function as shown by whole-cell patch-clamp recordings after transient expression in tsA-201 cells [95]. Mutation G407R, localized at the cytoplasmic end of segment IS6 (Fig. 2) results in a dramatic slowing of channel inactivation during prolonged depolarization, similar to mutations in CACNA1C (Cav1.2 α1) causing Timothy syndrome, a severe multi-organ disorder with high penetrance for autism [64].


Pharmacology of L-type Calcium Channels: Novel Drugs for Old Targets?
Human Cav1.3 mutations associated with ASD and PASNA. The transmembrane domain structure of Cav1.3 α1-subunit is illustrated. α1-subunits of voltage gated Ca2+ channels consist of four homologous repeats (I-IV), each comprising six transmembrane segments. Segments 1-4 of each domain form the voltage-sensor whereas segments 5 and 6 build the pore and activation gates. ASD-associated Cav1.3 mutations are highlighted in orange [68, 69, 117], PASNA-linked mutations shown in blue [70]. A59V, S1977L, and R2021H have not yet been analyzed functionally.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384371&req=5

Figure 2: Human Cav1.3 mutations associated with ASD and PASNA. The transmembrane domain structure of Cav1.3 α1-subunit is illustrated. α1-subunits of voltage gated Ca2+ channels consist of four homologous repeats (I-IV), each comprising six transmembrane segments. Segments 1-4 of each domain form the voltage-sensor whereas segments 5 and 6 build the pore and activation gates. ASD-associated Cav1.3 mutations are highlighted in orange [68, 69, 117], PASNA-linked mutations shown in blue [70]. A59V, S1977L, and R2021H have not yet been analyzed functionally.
Mentions: In addition to PD, inhibition of pathologically increased Cav1.3 activity may also be of therapeutic benefit in other brain disorders. We have recently reported that two de novo mutations in the CACNA1D gene (Cav1.3 α1-subunit) identified in humans with ASD cause a pronounced gain-of-channel-function as shown by whole-cell patch-clamp recordings after transient expression in tsA-201 cells [95]. Mutation G407R, localized at the cytoplasmic end of segment IS6 (Fig. 2) results in a dramatic slowing of channel inactivation during prolonged depolarization, similar to mutations in CACNA1C (Cav1.2 α1) causing Timothy syndrome, a severe multi-organ disorder with high penetrance for autism [64].

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