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

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.

Fig. (1)

Distinct biophysical and pharmacological properties of Cav1.2 and Cav1.3. a, When heterologously expressed in tsA-201 cells Cav1.3_L 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 Cav1.3_L [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.

Fig. (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.

Fig. (3)

Cp8-induced change in gating kinetics of full-length rat Cav1.3 (rCav1.3_L) Ca²⁺ currents. rCav1.3_L α1-subunits were transiently expressed in tsA201 cells together with auxiliary β3- and α2δ1-subunits. a, Ca²⁺ currents were evoked by a 100-ms long depolarizing step from a holding potential of -90 mV to the voltage of maximal activation (V_max) with a frequency of 0.2 Hz using 15 mM Ca²⁺ as charge carrier. b, Representative trace showing the modulation by 50 μM Cp8, wash-out and subsequent block by 1 μM isradipine. A pronounced slowing of the activation time course after Cp8 application was observed. c, Amplitude and width of tail currents were dramatically increased by Cp8. Subsequent wash-out could partially reverse this effect. The arrow indicates the peak of the tail current after wash-out. For details see [112].