Plasma membrane Ca2+ pump

PMCA plasma-membrane Ca2+ pump SCIP suppressed cyclic AMP-inducible POU domain protein... 

The cytosolic concentration of free Ca2+ is generally at or below 100 mi, far lower than that in the surrounding medium, whether pond water or blood plasma. The ubiquitous occurrence of inorganic phosphates (Pj and I l ,) at millimolar concentrations in the cytosol necessitates a low cytosolic Ca2+ concentration, because inorganic phosphate combines with calcium to form relatively insoluble calcium phosphates. Calcium ions are pumped out of the cytosol by a P-type ATPase, the plasma membrane Ca2+ pump. Another P-type Ca2+ pump in the endoplasmic reticulum moves Ca2+ into the ER lumen, a compartment separate from the cytosol. In myocytes, Ca2+ is normally sequestered in a specialized form of endoplasmic reticulum called the sarcoplasmic reticulum. The sarcoplasmic and endoplasmic reticulum calcium (SERCA) pumps are closely related in structure and mechanism, and both are inhibited by the tumor-promoting agent thapsigargin, which does not affect the plasma membrane Ca2+ pump. 

H-Arg-Lys-Asp-Val-Phe(4-Tmd)-OH plasma membrane Ca2+ pump-derived sequence, calmodulin-binding solid phase Fmoc/tBu, DIC/HOBt [1231... 

Brini, M., Coletto, L., Pierobon, N., Kraev, N., Guerini, D., Carafoli, E., 2003, A comparative functional analysis of plasma membrane Ca2+ pump isoforms in intact cells. J Biol Chem 278, 24500-24508. 

Lehotsky, J., Kaplan, P., Murin, R., Raeymaekers, L., 2002, The role of plasma membrane Ca2+ pumps (PMCAs) in pathologies of mammalian cells. Front Biosci 7, 53-84. 

Penniston, J.T., Enyedi, A., 1998, Modulation of the Plasma Membrane Ca2+ Pump. J Membr Biol VI65, 101-109. 

Strehler, E.E. (1991). Recent advances in the molecular characterization of plasma membrane Ca2+ pumps. J. Membr. Biol. 120, 1-15. 

Induction of the MPT requires Ca2+ conversely, plasma membrane and ER Ca2+ pumps require ATP. One of the earliest effects of CCb is metabolism-dependent inhibition of the ER Ca2+ pump through oxidation of a critical -SH residue. A similar oxidant-sensitive -SH residue is present in the plasma membrane Ca2+ pump. Thus, the reciprocal requirements of Ca2+ for the MPT and ATP for cellular Ca2+ pumps provide a mechanism for linkage of ATP depletion and disruption of Ca2+ homeostasis as mediators of cell death. Most proximal toxic effects that lead to hepatocellular mitochondrial and Ca2+ dysfunction can be generalized into two classes, those involving production of oxidative stress or formation of reactive metabolites. 

The primary plasma-membrane Ca2+ transporter (PMCA) is a P-type pump with high affinity for Ca2+ (Km = 100-200 nmol/1) but relatively low transport capacity [19]. The stoichiometry of PMCA is one Ca2+ transported for each ATP hydrolyzed. These pumps probably do not carry out bulk movements of Ca2+ but are most effective in maintaining very low concentrations of cytosolic Ca2+ in resting cells. A distinguishing characteristic of the PMCAs is that, in addition to binding Ca2+ as a substrate, they are further activated by binding... 

The plasma membrane Ca2+-ATPase pump effects outward transport of Ca2+ against a large electrochemical gradient for Ca2+. The mechanism of the pump involves its phosphorylation by ATP and the formation of a high-energy intermediate. This basic mechanism is similar for both the plasma membrane and ER pumps however, the structures of these distinct gene products are substantially different. As discussed below, the ER pump, sometimes called a sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) pump, is inhibited potently by certain natural and synthetic toxins that do not affect the plasma membrane pump. The plasma membrane pump, but not the SERCA pump, is controlled in part by Ca2+ calmodulin, allowing for rapid activation when cytoplasmic Ca2+ rises. 

As both fast and slow adaptation mechanisms are regulated by Ca2+, the stereocilia mechanisms that control the free concentration of this ion also play central roles in transduction. Entering Ca2+ is thought to be buffered very rapidly by the mobile buffers parvalbumin 3, calbindin, and calretinin [22,23]. Even before bound Ca2+ can diffuse out of stereocilia, it is pumped back out into the endo-lymph by isoform 2a of the plasma-membrane Ca2+-ATPase (PMCA2) [24,25] (see also Ca2+ transport in Ch. 5). 

Figure 11.8). In addition, the activated enzyme phosphorylates itself, and thus remains partly active even after the Ca2+ concentration falls and calmodulin is released from the enzyme. In contrast to the CaM kinases, another important target of Ca2+-cahnodulin is the plasma membrane Ca2+-ATPase pump, whose activation drives down the Ca2+ concentration within the cell, helping to terminate the signal. 

Sorin, A., Rosas, G., and Rao, R., 1997, PMR1, a Ca2+-ATPase in yeast Golgi, has properties distinct from sarco/endoplasmic reticulum and plasma membrane calcium pumps. J. Biol. Chem. 272, 9895-9901... 

Fig. 2. A schematic representation of some of the mechanisms by which Car fluxes across the plasma membrane are regulated. In the plasma membrane (the striped area) there are both influx (=>) and energy-dependent ( ) efflux pathways. Two mechanisms by which Ca2+ influx can be increased are via the actions of the intracellular messengers inositol 1,3,4,5-tetrakisphosphate, and cAMP generated via activation of specific classes of surface receptors (R, and R2) linked to specific N proteins which activate either phosphatidylinositol 4,5-bisphosphate (PIP,) hydrolysis or adenylate cyclase (AC). Additionally, influx can be increased either by a direct receptor-coupled event or by a membrane depolarization (not shown). A rise in the Ca2+ concentration in the domain just beneath the plasma membrane, [Ca2+Isin, can lead to an activation of the Ca2+ pump either via a direct calmodulin (CaM)-dependent mechanism, or indirectly via the activation of protein kinase C (CK). Additionally, in some cells, an increase in cGMP concentration also increases Ca2+ efflux (not shown), and in still others cAMP may stimulate Ca2 efflux.

In addition to mobilizing internal Ca2+, glucagon promotes the net entry of extracellular Ca2+ into hepatocytes [144,145]. The effect is apparently due to increased influx of Ca2+ through a plasma membrane channel(s) [144,145], but there is also inhibition of the plasma membrane Ca2+ ATPase-pump [150-153], The mechanism by which glucagon stimulates Ca2+ entry is unknown, but it almost certainly involves cAMP since the effect can be mimicked by forskolin, dibutyryl cAMP and /3-adrenergic agonists [144,145]. It may involve cAMP-dependent phosphorylation of a Ca2+ channel analogous to the situation in cardiac and skeletal muscle [154-156], but this is strictly speculative. 

Ca2+-ATPases exist in the plasma membranes of most cells and in the sarcoplasmic reticulum of myocytes, where they pump Ca2+out of the cytosol and into the lumen, respectively, while simultaneously counterporting H+ions. Ca2+-ATPase requires Mg2+on the side from which Ca2+is pumped. It is generally established that the Ca2+/ATP stoichiometries for the plasma membrane and sarcoplasmic reticulum are 1 and 2, respectively. Using a nonequilibrium thermodynamics model, the extent of slippage in the plasma membrane Ca2+-ATPase can be estimated from steady-state H+flow measurements. 

Calderaro V, Boccellino M, Cirillo G, Quagliuolo L, Cirillo D, Giovane A. Cyclosporine A amplifies Ca2-i- signaling pathway in LLC-PKl cells through the inhibition of plasma membrane Ca2-i- pump. J Am Soc Nephrol 2003 14 1435-1442. 

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