Calcium-Phosphate Metabolism and Derrangment Flashcards
About how much Ca2+ input is their per day?
• what are the main modes of output?
Input:
1000 mg
Output:
• Fecal Loss - 700 mg
• Renal Excretion - 300 mg
What is the normal range for serum Calcium?
• ionized Ca2+ component?
Serum Calcium conc. = 8.7 to 10.2 mg/dL
Ionized calcium component = 4.8 to 5.2 mg/dL
What is the distribution of most Ca2+ that is not sequested in the bone?
• what is the active component?
1% not sequestered in Bone
MOST = intracellular
Extracellular: • 45% protein Bound • 55% non-protein bound -------> 45% Free Ionized*****ACTIVE****** -------> 10% complexed
How does calcium penetrate into an enterocyte from the GI tract?
•how does it exit the basolateral side?
• TRPV6 Channel used by Ca2+ from the brush border membrane along a the electrochrmical gradient.
Basolateral Side:
• Pumped OUT (uphill) by ATP powered Ca2+ pump (aka Ca2+ ATPase)
Compare the way that calcium leaves the cell on the basolateral side in times of normal intracytoplasmic calcium levels vs. when intracytoplasmic Ca2+ is super elevated.
Normal Ca2+ exit through the Basolateral Side:
• ATP powered Ca2+ ATPase pump pushes Calcium out into the blood
Elevated intracytoplasmic Ca2+ levels:
• Leaves the cell using the Na+/Ca2+ exchanger
What regulates the passive influx and efflux of Ca2+?
• what does this do?
- Passive Ca2+ influx and efflux are regulated by Calcitriol
* Calcitriol Binds the Vitamin D receptor
What parts of the filtration apparatus in the kidney play an important role in fine tuning renal excretion of Ca2+?
Distal Convoluted Tubule (DCT) Connecting Tubule (CNT)
What Ca2+ channels/transporters are present on the Apical and Basolateral Membrane of cells in the DCT and Connecting Tubule?
Apical Membrane:
• TRPV5 => Ca2+ channel
Basolateral:
• NCX1 - Na+/Ca2+ exchanger on the basolateral side of the cell
•PMCA1 - ATP driven Ca2+ transporter
What role would increased activity of PTH-R and and NKA play in Ca2+ transport in the Kidney?
PTH-R:
• PTH stimulates the Receptor on the BASOLATERAL side of the DCT/CNT and stimulates activity of TRPV5.
NKA (sodium-potassium ATPase)
• Increased activity raises intracellular Na+ levels which means more Ca2+ export
What does Klotho do?
- Acts on the Basolateral membrane to upregulate NKA activity and thus NCX1 activity.
- Acts on Apical Membrane to increase TPRV5 activity
What role does BK2 play in Ca2+ import?
• which side of the cell is it found on?
BK2
• Stimulated by TK (Tissue Kallikrien) to activate TRPV5
What are the steps in suppression of PTH?
HIGH CALCIUM in serum =>
1. CaSR (calcium-sensing receptor) = GPCR
- Stimulation = release of Phospholipase C leading to increased IP3
- this INHIBITS PTH synthesis and secretion
What happens in the parathyroid cells when serum calcium is low?
LOW CALCIUM in serum =>
1. Inhibition of intracellular signaling
- Increased PTH synthesis and secretion
What is the distribution of phosphorus in the body?
Bone - 85%
Soft Tissue - 14%
Extracellular Fluid - 1%
What are the main forms of Phosphorus in the plasma?
• ratio at physiological pH?
HPO4– and H2PO4- are present in a 4:1 ratio at pH 7.4
What is the amount total phosphorus taken in per day?
• how much is absorbed at different levels of intake?
Phosphorus per day:
• 800 - 1500 mg
How much absorbed:
• at more than 10 mg/kg/day 70% absorbed
• at less than 10 mg/kg/day 80-90% absorbed
Important to recognize that we are good at reabsorbing phosphorus because we need it for everything*
What are the normal serum levels of phosphorus?
2.5 to 4.5 mg/dL in people with a GFR greater than 25 mL/min
How much of dietary phosphorus is typically elminated?
• when do you see hyperphosphatemia?
typically 5-15% is eliminated daily
Only time you see too much phosphate in serum is with severe renal insufficiency (GFR less than 25 mL/min
What is the main method of phosphate loss (for someone with a daily intake of 1400mg)?
• in what ways is this different than Ca2+ elimination?
Renal Excretion - 900 mg
Fecal Excretion - 500 mg
Most Ca2+ is excreted in the Feces while most PO4 is excreted in the urine
What is the difference in the S1, S2, S3 portions of the proximal convoluted tubule as far as Phosphate Transporters go?
S1/S2 - Apical:
• 3Na+/HPO4- co-transporter
• 2Na+/HPO4- co-transporter
• 2Na+/H2PO4- co-transporter
S3 - Apical:
• 3Na+/HPO4- co-transporter
• 2Na+/H2PO4 co-transporter
BOTH BASOLATERAL:
• H2PO4-/HPO4- (unknown) channel
• NKA = DRIVES THE Na+ gradient
Where is most PO4 reabsorbed in the nephron?
Proximal Tubule = most common sight of reabsorption
T or F: tubular reabsorption of phosphate is saturable
True, look at diagrams to see a graph of this
How do we know that phosphate reabsorption is saturable?
• it is excreted LINEARLY with PLASMA concentration and depends on GFR
if we compare it to inulin it will have the same slope just shifted down to account for the set amount of reabsorption that’s occuring
T or F: Vitamin D is an important hormone needed to regulate Ca2+ and Cl- homeostasis.
FALSE, Vitamin D is a PROHORMONE needed to regulate Ca2+ and PHOSPHORUS homeostasis
What are the steps in the endogenous formation of Vitamin D3?
Cholesterol => 7-dehydrocholesterol + Sunlight/UVB => Vitamin D3
What allows Vit. D3 to travel in the bloodstream?
• where is it delivered 1st?
Vit. D Binding Protein (VDBP) binds to Vit. D and carries Vit. D3 to the LIVER to be acted on by 25-hydroxylase
What are the 4 main places 1,25-(OH)2D - Active Vit. D is delivered?
- Intestine
- PTH gland
- Osteoclast Precursors
- Kidney
What receptors on kidney cells bind VDBP-25(OH)D?
- Cubulin
* Megalin
What Happens when Vitamin D enters a target cell?
Transcriptional Effects:
• Binds VDR (vitamin D receptor and diffuses into nucleus)
• Binds VDR-1,25(OH)2D binds RXR on DNA and upregulates transcription of proteins
Conversion of Calcitriol:
• CYPs act on 1,25 (OH)D2 (calcitriol) to turn it into calcitriolic acid
What are 3 factors that DOWN REGULATE PTH?
• how do they work?
- Calcium => CaSR activation –> Ca2+ release from ER —> Less PTH secretion
- Calcitriol - 1) preproPTH transcription inhibition via VDR 2) also upregulates CaSR to indirectly inhibit
- FGF23 - Direct inhibition of PTH mRNA generation
What are 3 factors that UP REGULATE PTH?
• Explain how they work
- High Phosphorus => PTH mRNA stabilization –> increased PTH
- Low Calcium 1) Direct DECREASE in CaSR activation 2) High Ca Calreticulin INHIBITS calcitriol
- FGF23 - decrease Calcitriol Synthesis
How is PTH stored?
• what is its half-life?
PTH is stored in granules inside the gland
• Half-life = 2-4 min
What type of receptor is the PTH receptor?
• where is it expressed?
PTH Receptor = GPCR
Acts via cAMP => PKA => PKC => Increased Intracellular Ca
Where is it expressed?
• Lots of tissues express the receptor IMPORTANTLY the kidney does too
What is the MOST IMPORTANT END ORGAN of PTH action?
• specific cells within this organ?
BONE!!!!
• Specifically OSTEOBLASTS
T or F: PTH effects on bone differ depending on if PTH1R stimulation is chronic or pulsitile.
TRUE
What allows FGF23 to circulate and act as an endocrine whereas other FGFs outside of its family cannot do this?
• what does FGF23 do - broadly?
• Chromosomal Location
- FGF 19, 21, 23 = Heparin Independent
- FGF23 = phosphate and Vit. D homeostasis
Chromosome:
• 12p13
What is the primary area of expression for FGF23?
- PREDOMINANTLY OSTEOCYTES
* ventrolateral thalamic nucleus, central venous sinusoids and thymus
What are the Two KEY functions of FGF23?
- Phosphaturic
2. Suppressor of 1-alpha hydroxylase in the kidney
What organ expresses the greatest amount of FGF23?
BONE - because osteocytes are the primary cell in this tissue
What Co-Factor is important for the actions of FGF23?
• where is it expressed?
Klotho
• Highly expressed in the tissues targeted by FGF23 but NOT in other tissue
What is Klotho?
• SIngle-pass TM protein necessary for FGF23 mediated receptor activation
What is the action of FGF23 in the kidney?
- Reduced Renal Phosphate Reabsorption
- Reduced 1-alpha-hydroxylase activity
- Prevents soft tissue calcification
- Tumor calcinosis in some pts. with mutations
How does FGF23 prevent renal phosphate reabsorption?
• Sodium Dependent Phosphate Reabsorption
What role does paracellular transport play in the movement of calcium? when?
• where does this happen?
Paracellular Transport of Ca2+ becomes important when TRPV6 gets saturated in JEJUNUM after a high Calcium Meal.
Looks like this only happens in the GI tract
What is calbindin?
Intracellular Transporter of Ca2+ inside of cells in the kidney (Distal Convoluted Tubule and Connecting Tubule)
T or F: Despite gaining tons of calcium during childhood and adolescence, serum Ca2+ concentrations stay pretty much the same.
True, our bodies are good at regulating blood levels of Ca2+
What is the only part of the nephron not involved in Ca2+ uptake?
Ascending Limbs of the LOH
T or F: Vitamin D is a prohormone that needs to be activated.
True, Vitamin D itself is not active
What is the STONGEST stimulator of PTH production?
LOW CALCIUM
