(a) What are peptide hormones ? With the help of schematic diagram, discuss the epinephrine cascade for the glucose release from…

(a) Peptide hormones and the epinephrine cascade for glucose release from hepatocytes

Peptide hormones (insulin, glucagon, ACTH, oxytocin, growth hormone) are chains of amino acids, water-soluble and stored in vesicles, which cannot cross the plasma membrane. They bind receptors on the cell surface and act through second messengers. Epinephrine, a catecholamine, acts in the same way on liver cells, using a G-protein-coupled receptor.

The cascade (see the figure below):

1. Epinephrine binds the β₂-adrenergic receptor on the hepatocyte, which exchanges GDP for GTP on the Gαs subunit of the G protein.
2. Gαs–GTP leaves Gβγ and activates adenylyl cyclase, which converts ATP to cAMP.
3. cAMP binds the regulatory subunits of protein kinase A (PKA) and releases its active catalytic subunits.
4. PKA phosphorylates and activates phosphorylase kinase, which phosphorylates glycogen phosphorylase b to the active form a. PKA also inactivates glycogen synthase.
5. Glycogen phosphorylase a splits glycogen into glucose-1-phosphate, which phosphoglucomutase changes to glucose-6-phosphate.
6. Glucose-6-phosphatase, present in liver, removes the phosphate, and free glucose leaves through GLUT2 into the blood.

Each step amplifies the signal, so a few hormone molecules mobilise much glycogen. The signal ends when Gαs hydrolyses GTP, phosphodiesterase breaks down cAMP and phosphatases reverse the phosphorylations.

(b) Cyclic AMP as a second messenger

Sutherland showed that a hormone (the first messenger) acts at the cell surface, and cAMP formed inside the cell carries the message. It qualifies as a second messenger because:

• it is made inside the cell by adenylyl cyclase only after the hormone binds the receptor;
• it is small and hydrophilic, so it diffuses quickly through the cytosol;
• it amplifies the signal, since one receptor activates many G proteins and each cyclase makes thousands of cAMP;
• it is removed quickly by phosphodiesterase (cAMP to 5′-AMP), so the response can be switched off;
• it acts on defined targets, mainly protein kinase A, and also Epac and cyclic-nucleotide-gated channels.

Importance, with an example: the action of ACTH on the adrenal cortex. ACTH binds the melanocortin-2 receptor, which activates Gs and adenylyl cyclase; the rise in cAMP activates PKA, which phosphorylates hormone-sensitive lipase and StAR protein, so cholesterol is delivered into mitochondria for cortisol synthesis. In the same way, glucagon and epinephrine use cAMP for glycogen breakdown in liver, TSH for thyroid hormone release and FSH for oestrogen production, and cAMP also regulates gene expression through CREB.

(c) Bioenergetics and the second law of thermodynamics in energy transduction

Bioenergetics is the study of energy flow and conversion in living systems. Free energy is governed by ΔG = ΔH − TΔS, where a reaction is spontaneous if ΔG is negative.

The second law states that in any spontaneous process the entropy of the universe increases, and energy conversions are never 100% efficient. A cell is an open system that keeps its order (low entropy) by taking in energy and releasing heat and simpler molecules, so that the entropy of the surroundings rises more than the cell's entropy falls. The role of the law in energy transduction:

• the energy of food or light is converted into useful work by coupling an energy-releasing (exergonic, ΔG negative) reaction to an energy-requiring (endergonic) one, with ATP as the common currency;
• in oxidative phosphorylation the electron flow down the respiratory chain pumps protons, and the proton gradient drives ATP synthase;
• every conversion loses part of the energy as heat (TΔS), so only a portion, about 40% in the oxidation of glucose, is trapped in ATP;
• hence energy flows one way through ecosystems, and life needs a continuous supply of energy.