G-protein coupled receptors

G protein coupled receptors have an extracellular binding site to which the hormone binds and an intracellular cytoplasmic tail region to which G-proteins may bind.  

G proteins act as a switch and functionally couple the receptor to their target enzymes or ion channels. Switch means there is an inactive state when the hormone is not bound to the receptor and when the hormone binds, there is activation. G-proteins or heterotrimeric GTP binding proteins is a set of 3 proteins, G alpha, G beta and G- gamma which are present as an inactive complex bound to membrane just near the hormone receptor.   

The alpha subunit of G proteins is bound to GDP in inactive state.When the hormone binds to its receptor, receptor interacts with the G proteins and GDP bound to alpha subunit is replaced by GTP, which is now said to be in active state. This replacement of GDP with GTP causes alpha subunit to dissociate from beta and gamma subunits and move and associate with some other proteins causing  either opening/closing of ion channels or they affect the activity of enzymes like adenyl cyclase and phospholipase C. 

G proteins which stimulate adenyl cyclase activity are known as G stimulatory proteins i.e Galpha s. while that which inhibits their activity ate known as inhibitory G proteins i.e Galphai. The G proteins which affect the activity of phospholipase C are known as G q proteins. The effect of the hormone on the cell depends on the type of the receptor it binds for e.g. same hormone in one cell may have a receptor which is linked to stimulatory G proteins while in other cells it may have a receptor which is linked to inhibitory G proteins. By the change in the activity of these enzymes, second messenger systems or we can say signalling pathways are activated. 

 Adenylcyclase-cAMP pathway 

When adenyl cyclase enzyme is activated, it causes the conversion of ATP to cAMP. cAMP in turn cause the activation of cAMP dependent protein kinase A which causes phosphorylation of some proteins/enzymes in the cell. Now these proteins may be involved in biological reactions or these phosphorylated protein inturn activate or inhibit other proteins which are involved in cellular reactions. So ultimately this process affects the function of the cells. In addition,PKA can also increase/decrease the transcription of some genes.Close to these genes, is present a region known as cAMP-responsive element (CRE) region of DNA.  A subunit of PKA moves to the nucleus and phosphorylates another protein, the cAMP-responsive element binding protein (i,e CREB protein) which then binds to CRE and alters transcription of the genes where CRE is present. The set of proteins activated by cAMP varies in different cells. So adenyl cyclase activation  in different cells leads to different actions. However if same adenyl cyclase is activated by different ligands in the same cell, it leads to same actions. So in this pathway, cAMP acts as a second messenger.

Phospholipase C-IP3-DAG-Calmodulin pathway 

 When phospholipase C is activated by Gq proteins, it causes breakdown of the membrane phospholipid phosphatidylinositol 4,5 bi or di phosphate (PIP2) into IP3, i.e inositol triphosphate and Diacyl glycerol (DAG). Ip3 acts on IP3 receptor (IP3R) present on endoplasmic reticulum. This IP3R is itself a ligand gated calcium channel. When IP3 binds, it opens up causing release of calcium ions from ER into the cytososl. The calcium ions in turn bind with calmodulin causing activation/inhibition of calmodulin dependent protein kinases.  

DAG activates protein kinase C which then phosphorylates other proteins just as we saw for adenyl cyclase dependent kinases. So in this case IP3, DAG and calcium are second messengers.

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Weber Fechner and Steven's Power law

The concept of Just Noticeable Difference was given by Weber where he explained that we will be able to perceive the difference in intensity of the stimulus depending on the original strength of the stimulus. For higher strengths of stimulus, a greater chnage in intensity of stimulus is required is required to notice the difference in intensities. 

Fechner took this concept and tried to explain the percieved intensity of stimulus vis a vis the strength of stimulus. But Fechner law was applicable to only very high and very low intensities of stimulus. Later this was modified by Steven who gave Power law to explain the percieved intensity of stimulus.


Watch the video for details....

Classification of sensory receptors

Afferent neurons transmit action potential from the periphery to the central nervous system. These afferent neurons have sensory receptors at their peripheral endings. Receptors as the term indicates receive information or we can say characteristics of a stimulus from the surroundings. 

The stimuli are of various types depending on the type of energy change for e.g. there can be either mechanical stimulus , chemical stimulus or thermal stimulus etc. Body has receptors for detecting different types of energies. But once the receptors detect the stimulus, it has to be transmitted to the CNS as action potential, so receptors convert the stimulus energy into electrical signals. This is known as signal transduction.  

Sensory Receptors can be classified in 3 ways

1. Based on their location: exteroceptors, interoceptors and proprioceptors

2. Based on modality of stimulus they detect: mechanoreceptors, chemoreceptors, thermoreceptors, nociceptors, and electromagnetic receptors . 

3. Based on rate of adaptation: Slowly adapting receptors and fast adapting receptors.

In skin , their are various mechanoreceptors. However, they are located in various layers of skin e.g. Merke;'s disks are located superficially in dermis and detect superficial texture of the object while Ruffini ending is deeper in dermis and detects pressure. 

Also there are Meissner’s corpuscle versus Pacinian corpuscles. Both these receptors adapt very fast. Thus, they detect vibration sense. But, meissner’s corpuscle respond to slow vibration while pacinican corpuscle respond to fast vibration because pacinian corpuscle adapt very very fast. And pacinican corpuscles are located deep so they respond to deep pressure vibration while Meissner’s has to be superficial like a flutter on the skin. Also, meissner’s corpuscles detect the sensation from a small superficial area while Pacinian corpuscle respond to a stimulus even when it is present in a little larger area. This is known as receptive field of the receptor.

Starling's forces and physiological basis of edema

Starling's forces

1. Capillary hydrostatic pressure

2. Capillary oncotic pressure

3. Interstitial fluid hydrostatic pressure

4. Interstitial fluid oncotic pressure

Forces at arterial end of capillary

Starling's Forces promoting filtration: 

1. Hydrostatic capillary pressure: 32 mmHg 

2. Interstitial oncotic pressure: 8 mmHg (due to proteins)

3. Interstitial hydrostatic pressure: -3 mmHg (Some fluid is also present in interstitial space. However, due to pulling by the tissues, a negative hydrostatic pressure is generated in interstitial space. So, it promotes filtration)

Total =  43 mmHg (by adding all forces)

Forces opposing filtration

2. Oncotic capillary pressure: 28 mmHg

Net driving force at arterial end of capillaries = Forces promoting filtration - Forces oppsong filtration

                               =  43-28 = 15 mmHg

Since it is a positive force, it drives water movement out of the capillaries.

Starling's Forces at venous end of capillary: 

Starling's Forces promoting filtration: 

1. Hydrostatic capillary pressure: 10 mmHg   (hydrostatic pressure decreased due to the movement of water outside the capillaries at the arterial end

2. Interstitial oncotic pressure: 8 mmHg (due to proteins)

3. Interstitial hydrostatic pressure: -3 mmHg 

Total =  21 mmHg (by adding all forces)

Forces opposing filtration

1. Oncotic capillary pressure: 28 mmHg

Net driving force at arterial end of capillaries = Forces promoting filtration - Forces oppsong filtration

                               =  21-28 = -7 mmHg

Since it is a negative force that means it draws in water into the capillaries. So there is the inward pull of water at the venous end. 

That means water which is filtered at the arterial end is reabsorbed at the venous end. 

But at arterial end, the net outward force was 15 mmHg and at the venous end, the net inward force was 7 mmHg so some fluid remains in the interstitial space. Lymphatics carry that excess fluid from the interstitial space. 

Now when can fluid accumulate inside interstitial space? That extra fluid accumulation in interstitial space is known as EDEMA. 

 So when can oedema occur? 

1. Increased hydrostatic pressure occurs in the case of hypertension or excess fluid accumulation. ( heart failure or iatrogenic) 

2. Decreased oncotic pressure that is due to decreased protein concentration. 

It may happen due to:

Malnutrition: Decreased protein intake 

Malabsorption: Decreased protein absorption

Liver disease: Decreased synthesis of proteins

Kidney disease: Increased loss of proteins

3. Increased capillary permeability can occur in case of local injury.

4. Blocked lymphatics can occur in case of filariasis, metastasis of cancerous cells to lymph nodes 

Edema is of 2 types

1. Transudate: This means that it is the water that is being accumulated inside the interstitial space. 

2. Exudate: along with water, there is a movement of proteins also from the capillary.  So exudate is water plus proteins. It occurs when there is increased permeability of capillaries causing movement of proteins also out of the capillaries.

Countercurrent mechanism | Concentration and dilutio of urine

Kidneys need to excrete concentrated or dilute urine depending on the hydration status of the body. The concentration or dilution of urine depends on the presence of a gradient of hyper osmolarity in medullary interstitium. Basic function of countercurrent mechanism is to make the medullary interstitium hypertonic. Ultimately, it will help in excretion of a concentrated or dilute urine as required.  

So, there are aspects 1) Generation of hypertonic gradient in medullary interestitium: By countercurrent multiplier 2) Maintenance of hypertonic gradient in medullary interstitium: BY countercurrent exchanger  

Generation of gradient occurs by countercurrent multiplier and maintenance of gradient is done by countercurrent exchanger

Countercurrent multiplier: Occurs in juxtamedullary nephrons

Ascending limb of LOH is permeable to solutes only and descending limb is permeable to water only. 

Permeability in thick ascending limb to solutes is by active transport by transporter Na+K+2Cl- present on the apical membrane of cells of thick ascending limb. Permeability to water in descending limb is passive.  

The fluid which filters through the Bowman’s capsule has the same osmolarity as that of blood i.e 300 mOsm/L of fluid. Now we are considering the first time as fluid passes through the nephron.. So everywhere osmolarity is 300 mOSm/L. Now as the filtered fluid of 300 mosm/l osmolarity passes through the nephron, even though it passes through the descending limb, there will be no net movement of water because the osmolarity is same everywhere. 

As the filtrate passes through the ascending limb, the Na+K+2Cl- transporter, starts throwing out these ions into the interstitium since it is active transport. Because of this, the osmolarity of interstitium increases and osmolarity of fluid in the nephron decreases. So fluid in the nephron becomes hypotonic. Now this effect on osmolarity of medullary interstitium by passing of fluid in the nephron is known as Single Effect.  

As second cycle of fluid passes through the descending limb, because of the first cycle there is a gradient for water to move. So passive movement of water occurs from descending limb into the medullary interstitium and the osmolarity of tubular fluid increases.  

Now as the hypertonic fluid of nephron passes through the ascending limb , Na K+2cl- throws out more and more ions, decreasing the osmolarity of the tubular fluid while increasing the osmolarity in medullary interstitium. So this will create a gradient of osmolarity in medullary interstitium.  

This medullary osmolarity keeps on increasing with each cycle of fluid passing. So this is multiplication of the single effect and the osmolarity keeps on increasing until 1200 mOsm/L.

Countercurrent exchanger: Role of vasa recta

The osmolarity of the blood is 300 mOsm/L. The capillary bents into a U shape. In vasa recta, water moves out of the capillary while salt moves into the capillary in descending limb while opposite movement of water and salt occurs in ascending limb. So, this is how gradient in medullary interstitium is maintained.

Concentration and dilution of urine

Because of generation of medullary hyperosmolarity, end result is presence of hypoosmolar tubular fluid in DCT, is hypo-osmotic , so a dilute urine is excreted. However to concentrate urine, we need ADH ADH increases the permeability of cells to water in last part of distal tubules, collecting tubules and collecting ducts. Only if medullary interstitium is hyperosmolar, water will move from nephrons into the medullary interstitium and then into the blood. 

So for concentration urine, ADH and hyperosmolar medullary gradient is needed.

Treatment approach for tachyarrhythmias

Treatment approach for tachyarrhythmias 

Based on their origin, tachyarrhythmias are classified into 

 1. Ventricular tachyarrhythmias 

 2.Supra ventricular tachyarrhythmias.. i.e due to origin above the ventricles 

Treatment strategy for tachyarrhythmias differs depending on the cause of increased ventricular rate. If any interference has to be made for atria or ventricles cells, we use class I or Class III antiarrhythmic drugs. In arrhythmias which occur due to pacemaker cells i.e SA node or involve AV node ,we use Class II or class IV antiarrhythmic drugs. So basically these 2 classes of drugs are used for Supraventricular arrhythmias that are caused in SA node or due to excessive conduction of impulses through AV node. 

        Supra ventricular causes of tacharrhythmias

 In case of supra ventricular arrhythmias, cause can be at the level of SA node or atria or AV node pathway

 1. At the level of SA node: inappropriate tachycardia: For treating SA node arrhythmia we may use either Class II drugs i.e beta blockers  or class IV drugs i.e calcium channel blockers 

 2. Atrial causes of tachyarrhythmias.: It may be either atrial flutter or fibrillation For AF/AFi, we need to decrease the number of impulses being conducted to ventricle. This is done by class II or class IV antiarrhythmics. It does not terminate the arrhthmia as such but decreases  the number of impulses  conducted to ventricles. 

But if, ventricular rate cannot be controlled or the patient experiences symptoms like palpitation or the patient is hemodynamically unstable, we need to revert to sinus rhythm..i.e terminate the arrhythmias. If it is an emergency condition: electrical cardio version is done class Ic i.e propafenone or class III drugs dofetilide may be used: a. In case if it is not an emergency but the patient is experiencing the symptoms b. the in case the condition is recurrent tomaintain sinus rhythm For prolonged treatment for recurrent AF or atrial fibrillation, another class III drug amiadarone is used Also ablation of the focus with readiofrequency waves may be done.. 

 3. Reentry arrhythmias- it may be either AV nodal reentry arrhythmias or Atrio-ventricular reentry arrhythmias. 

 In AV nodal reentry, both fast and slow pathways are present in the conducting pathways involving AV node. For the treatment,  Initially vagal manoeuvres are sought which decrease the RMP. or IC adenosine is gicen which also  hyperpolarizes the tissue, making them less excitable. 

 For Atrioventricular reentry, where there is an accessory pathway between the atria and the ventricles,  use potassium channel blockers i.e class III drugs which will prevent the ventricular cells from getting depolarised and class I drugs which will increase the threshold. Again, vagal monouvers and adenosine will hyperpolarize the tissue and may be used for termination of arrhythmias 

                                  

                                 Ventricular arrhythmias 

 1. Ventricular tachycardia: 

a. If the person is hemodynamically unstable we need to urgently use electrical cardioversion to bring revert him to sinus rhythm.

b. If VT is arising in an ischaemic tissue, we can use Class Ib drugs especially IV lidocaine.  

c. In case of recurrent VT we need to resort to long term treatment. Again for long term we have to use Class III drugs esp amiadorone. 

 2. Ventrciular fibrillation:  

a. For hemodynamically unstable case, we need to use electrical cardio version to revert them to sinus rhythm.

b. In case of recurrent VF, we need to implant a cardiac defibrillator i.e ICD in patient’s heart which senses the origin of the VF and delivers shocks to restore normal sinus rhythm.

c.  If the patient is not an ideal candidate for ICD we may use class IIII drug..amiadoarone to increase the refractory period and make the cells unresponsive so that reentry is not possible.

Physiological basis of action of antiaarhythmic drugs

There are 4 classes of antiarrhythmic drugs depending on which channels or receptors they block.

Class I drugs block sodium channels
Class II drugs are beta blockers
Class III drugs block K+ channels and
Class IV drugs are calcium channel blockers

 We should know first where on the cardiac action potentials, different classes of antiarrhthymic drugs will act…

Class I antiarrhythmic drugs: Sodium channel blocker i.e class I anti arrhythmic drugs increase the threshold for phase 0 of contractile cell action potential increases, …it also decreases the slope of phase 0. 
In class I there are 3 subclasses of drugs..
   There are different states of sodium channels …closed, open and inactivated.
        Class Ia drugs block sodium channels in open state
        Class Ib drugs block sodium channels in inactivated state… most important effect on already depolarised tissue as seen in ischemia
        Class Ic drugs block sodium channels in open state and also prolong the recovery time of channels 

Class II antiarrhythmic drugs: act on phase 4 of pacemaker action potential

Class III drugs i.e potassium channel blockers will act on the repolarization phase and prolong the duration of action potential

Class IV drugs i.e L type calcium channel blockers will act in phase 0 of action potential of pacemaker cells.

Tachyarrhythmias may occur either due to
Enhanced automaticty
Triggered automaticity
Reentry

Physiological basis of treatment of arrhythmias

 1. Enhanced automaticity: In arrhythmias due to enhanced automaticity, the slope of the prepotential becomes steeper may be due to enhanced sympathetic activity or the maximum diastolic potential becomes less negative


Basically to treat these arrhythmias you will want to decrease the rate of generation of impulse either by:
 a. decreasing the slope of this drift of phase 4 : beta blockers (Class II)
 b. Increasing the threshold for excitation… so phase 0 will start much above than usual threshold: Class IV for pacemaker cells or class I for contractile cells
c. Prolonging action potential duration: by potassium channel blockers
d. Increasing the negativity of RMP: by acetylcholine and adenosine