Calcium Homeostasis, Transporters, and Blockers in Health and Diseases of the Cardiovascular System

Abstract

Calcium is a highly positively charged ionic species. It regulates all cell types' functions and is an important second messenger that controls and triggers several mechanisms, including membrane stabilization, permeability, contraction, secretion, mitosis, intercellular communications, and in the activation of kinases and gene expression. Therefore, controlling calcium transport and its intracellular homeostasis in physiology leads to the healthy functioning of the biological system. However, abnormal extracellular and intracellular calcium homeostasis leads to cardiovascular, skeletal, immune, secretory diseases, and cancer. Therefore, the pharmacological control of calcium influx directly via calcium channels and exchangers and its outflow via calcium pumps and uptake by the ER/SR are crucial in treating calcium transport remodeling in pathology. Here, we mainly focused on selective calcium transporters and blockers in the cardiovascular system.

Keywords: Cav1; Cav2; Cav3; G protein; GPCR; L-type calcium channel; N-type calcium channel; P/Q-type calcium channel; R-type calcium channel; T-type calcium channel; calcium; calcium channel blockers; calcium homeostasis; calcium overload; calcium pumps; endoplasmic reticulum; hypercalcemia; mitochondria; nucleus; sodium/calcium exchanger.

Figure 3

Current to voltage (I/V) relationship curve (A) and open probability/voltage relationship (B) of the voltage-dependent steady-state R-type Ca²⁺ channel in human aortic VSMCs recorded using the patch clamp technique. Modified from [11,92].

Figure 1

Schematic representation of various calcium transporters. VOCCs, voltage-operated calcium channel; ROCC, receptor-operated calcium channel; TRPP-2, transient receptor potential polycystic 2; PLC, phospholipase C; DAG, diacylglycerol; ER, endoplasmic reticulum; NR, nucleoplasmic reticulum; RyR, ryanodine receptor; IP₃R, inositol 3 phosphate receptor; NPC, nuclear pore channel; GPCR, G-protein coupled receptor; TKR, tyrosine kinase receptor. Ca²⁺ in red represents the increase in calcium. The question mark (?) indicates that the nature of the single-channel conductance and the calcium selectivity of these ionic channels are unclear.

Figure 2

The whole-cell patch clamp technique shows examples of two types of Ca²⁺ currents in a human ventricular single cell. (A) Voltage-dependence of the low threshold of I_Ca (open circles) and separation of the high-threshold I_Ca (open triangles). (B) Peak current trace of the low-threshold I_Ca recorded from a holding potential (HP) of −80 mV with a voltage step (VS) to −10 mV. (C) Current trace of the high-threshold I_Ca was recorded from an HP of −50 mV with a VS to +20 mV. (D) Steady-state inactivation relationship of the low- (open circles) and high-threshold (open triangles) I_Ca. (E) Low-threshold current recorded from HP of −65 mV with a VS to −20 mV. (F) High-threshold current trace recorded from HP of −17 mV with a VS to +20 mV. Currents were measured at the peak (modified from [44]).

Figure 4

Using quantitative 3D confocal microscopy shows rapid time-lapse scans and graphic representations of cytosolic and nuclear free Ca²⁺ variations during spontaneous contraction in 10 day-old chick embryonic ventricular myocytes loaded with Ca²⁺ dye fluo-3. Whole-cell images show the relative fluorescence level and distribution of free Ca²⁺ during the propagation of Ca²⁺ waves. The graphic representations present the corresponding variations of the spontaneous waves of Ca²⁺ within the cytosol and the nucleus. The spontaneous wave of calcium quickly spreads across the cytosol and the nucleus. The free Ca²⁺ fluorescence intensity levels are particularly intense in the nuclear region and remain elevated even after cytosolic Ca²⁺ has returned to basal levels. The resting and peak levels of nuclear Ca²⁺ are higher than that of the cytosol. Spontaneous cytosolic and nuclear Ca²⁺ waves may have fast and slow decay components. Images are shown as pseudocolored representations according to the colored calibration bar of fluorescence intensity on a scale from 0 (black, absence of fluorescence) to 255 (white, maximal fluorescence) (modified from [17]).

Figure 5

Using whole-cell patch clamp technique blockade of the L-type Ca²⁺ current in a human ventricular single cell by PN 200-110 (isradipine). The L-type I_Ca was activated from a holding potential (HP) of −50 mV with a voltage step (VS) to +20 mV. Superfusion with 10⁻⁶ M PN 200-110 completely blocked the L-type I_Ca within 5 min ((A), open triangles and (B), current traces in the left panel). Inactivation of PN 200-110 with a flash of light returned the L-type I_Ca amplitude to the control level ((A), open square and (C), right panel current trace). After turning off the light, a very low concentration of PN 200-110 (10⁻⁹ M) decreases the L-type I_Ca by 88% within 11 min (close square and current trace in right panel) (modified from [44]).