Ca2+ leak

Mochizuki, M., Yano, M., Oda, T., Tateishi, H., Kobayashi, S., Yamamoto, T., Ikeda, Y., Ohkusa, T., Ikemoto, N., and Matsuzaki, M. (2007) Scavenging free radicals by low-dose carvedilol prevents redox-Dependent Ca2+ leak via stabilization of Ryanodine receptor in heart failure. J. Am. Coll. Cardiol. 49,1722-1732. 

Resting Ca2+ influx is attributed partly to a certain level of the open probability of excitable channels, including ROCs, SOCs and VGCCs. Some SOCs may stay open due to the basal level of InsP3, while the resting membrane potential of vascular smooth muscle allows for a certain degree of activation of the Ca2+ window current (Nelson et al 1990). Additionally a non-specific influx of Ca2+, referred to as the Ca2+ leak, substantially contributes to basal influx however, its precise mechanism remains elusive (van Breemen et al 1972). 

The large pore suggests that the primary state found in vivo is closed to avoid rundown of cation gradients across the plasma membrane and excessive Ca2+ leak from the endoplasmic reticulum stores. 

Nevertheless, most functional characterizations of RyR2 mutants performed so far agree on the presence of a diastolic SR Ca2+ leak upon (J-adrenergic stimulation and on a lower threshold for Ca2+ spilling from the SR. These dysfunctions are likely to promote the development of DADs and triggered arrhythmias in CPVT. 

Figure 7.1. Diagrammatic representation of cellular Ca2 movements. Calcium ions (Ca2 ) may cross the sarcolemma by the following routes (7) voltage-operated calcium channels Q) receptor-operated calcium channels ( ) fast sodium channels (7) Ca2 -A TPase pump (J) Na -Ca2 exchange and Ca2 + leak pathways. Inside the cell, Ca2 may be taken up into and released from mitochondria (MIT) and sarcoplasmic reticulum (SR) (8). Ca2 also binds to the intracellular proteins, calmodulin and troponin C. REC represents a specific membrane receptor site.

Ca2+ is the major second messenger in the activation of smooth muscle contraction. Thus smooth muscle Ca2+ handling is of major importance to understanding its function. Ca2+ homeostasis is a balance of Ca2+ influx and extrusion. Influx is generally through channels, such as I, or T type Ca2+ channels or the so-called capacitive entry pathway, through stretch activated channels, leak pathways and reversed mode Na+/Ca2+ exchanger, which may... 

The monomeric PLB mutant was as potent (actually even more so) than the native PLB, which indicated that a PLB pentamer forming a leak channel was unlikely. There is a reported backflux through the Ca-ATPase which is lower in the PLB knockout. In the heart you can make a really good SR vesicle preparation for direct evaluation of SR Ca2+ uptake, but one of the limitations here is that this is difficult for smooth muscle tissues, though the bladder is useful for some quantitative biochemistry. So the question of a PLB leak is still open for smooth muscle but, on the basis of cardiac data, it is unlikely. 

Phase 4 Hyperpolarization occurs before K+ efflux has completely stopped and is followed by a gradual drift towards threshold (pacemaker) potential. This is reflects a Na+ leak, T-type Ca2+ channels and a Na+/Ca2+ pump, which all encourage cations to enter the cell. The slope of your line during phase 4 is altered by sympathetic (increased gradient) and parasympathetic (decreased gradient) nervous system activity. 

Na+ Channel inactivation leading to Elevated action potential threshold Decreased nerve conduction and velocity Decreased Na+ leak and decreased likelihood of Na+ gradient collapse Stabilized Na+ gradient-linked transporters (glucose, creatine, Ca2+, H+, transmitters)... 

Waldeck et al. (1998a, 1998b) presented a nonequilibrium thermodynamics model for the calcium pump shown in Figure 11.4. This section summarizes this model. During the hydrolysis of ATP, a variation of the coupling stoichiometries with the electrochemical gradients is an indication of molecular slips. However, the Ca2+and H+membrane-leak... 

Figure 11.4. Schematics of calcium transport with Ca2+-ATPase liposome, ionophore (A), and leaks, lonophore A23187 induces uptake of Ca2+ions. Leaks are shown with dashed arrows, i is interior (alkaline) and e is exterior (acidic). Scalar flow of ATP hydrolysis...

By assuming, for the sake of simplicity, yCa = yH = 1, we may incorporate ATPase slips and the membrane leaks of H+ and Ca2+ into the definitions of phenomenological coefficients Zp s, LCab and LHb where the subscripts s and 1 refer to slip and leak, respectively, and we have the following flow-force equations in the matrix form... 

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