The Role Of G Protein Coupled Receptorss

Contractility of ASM requires an increased levels of intracellular Ca2+. When surface receptors are not activated, Ca2+ levels are low. Upon activation of these cell surface receptors by contractile agonists e.g. acetylcholine, serotonin and histamine, intracellular Ca2+ increases causing a contraction (9). Smooth muscle cell contraction is controlled by both receptor and mechanical activation of proteins actin and myosin and also changes to membrane potential.

Muscle contraction can be understood as the consequence of a process of transmission of action potentials from one neuron to another. A chemical called acetylcholine is the neurotransmitter released from the presynaptic neuron. As the postsynaptic cells on the muscle cell membrane receive the acetylcholine, the channels for the cations sodium and potassium are opened. These cations produce a net depolarization of the cell membrane and this electrical signal travels along the muscle fibers. Through the movement of calcium ions, the muscle action potential is taken into actual muscle contraction with the interaction of two types of proteins, actin and myosin.

-Sarcoplasmic Reticulum (SR) then releases Calcium which binds to troponin in the thin filament, exposing myosin-binding sites;

At the molecular level of explanation these processes are dependent on the interplay between glutamate receptors, Ca2+ channels, the increase of intracellular Ca2+ levels, Ca2+-dependent proteins like Akt, ERK, mTOR and neurotrophins such as brain derived neurotrophic factor (BDNF) (24, 25).

Smooth muscle contraction occurs when calcium is present in the smooth muscle cell and binds onto calmodulin to activate myosin light chain kinase (Wilson et al., 2002). Phosphorylation of myosin light chains result in myosin ATPase activity thus cross-bridge cycling occurs causing the muscle to contract (Horowitz et al., 1996). There are two known models of excitation and contraction in smooth muscle, electromechanical coupling (EMC) and pharmomechanical coupling

The body then detects that there is an increasing amount of ADP in the muscle cell.

For muscle to contract, actin and myosin filaments need to slide past each other, causing the sarcomere to shorten in length . Each myosin filament has a protruding bulbous head, which can bind with the binding sites on the

Increased intracellular calcium triggers the activation of calpain. Calpain, a calcium dependent proteolytic enzyme begins apoptosis (Momeni, 2011). Apoptosis occurs because calpain degrades the membrane, cytoskeleton, and the cell’s DNA. Calpain, in the presence of calpastatin, an endogenous inhibitor protein, unregulates calpain activation (Momeni, 2011). Calpain consists of a two catalytic subunits; within the 80kD subunit there are four domains, domains I through IV. Domains for calcium binding are found in first four EF-hands; the fifth EF-hand goes around the subunits thus creates a heterodimer interface (Todd, Moore, Deivanayagam, Lin, Chattopadhyay, Maki, Wang, & Narayana, 2003). During activation, domain I hydrolyses other proteins and these proteins go from the 80kD subunit to 30kD subunit (Suzuki, Hata, Kawbata, & Sorimachi 2004). After that, the active site cleft is rearranged because two calcium atoms bind (Suzuki, Hata, Kawbata, & Sorimachi

ith the myosin have been activated by the ATP, they will bind the action binding site.

Calcium needs to be released first and needs to be obtained in the body in order for the body to carry out its function. Calcium or calcium ion (Ca2+) is stored in the sacroplasmic reticulum (SR) to start contraction for the muscles.11 In the case of the cardiac muscle, it would start contraction through the Sodium-Calcium exchange (NCX) and with limited help of the SR. Sodium ions (Na+) would enter from the dyadic cleft, the space where the cell membrane and SR are in close proximity.11 This would cause Ca2+ to flow out of the cell. In order for Ca2+ to reenter it has to go through Ca2+ channels and so Ca2+ would be released.11 Excitation-contraction coupling relies on the dyadic cleft of Ca2+ to be released. Understanding how NCX works could help provide treatment for HF because the cardiac muscle could be manipulated to contract. It may be possible to remove the NCX because it can cause too much Ca2+ to be stored in the SR and cause arrhythmias and cell death.11 This would lead to a pathway to fixing any heart failure

I am conducting biomedical research in the laboratory of cardiac physiology under the mentorship of Dr. Elizabeth Murphy. Cardiovascular disease is the major cause of death in the US; therefore, a better understanding of the mechanisms regulating cardiomyocyte death in ischemia and reperfusion injury are important. Mitochondrial calcium plays a crucial role in the normal functioning of many processes, including the regulation of cardiac biochemical pathways and mediating ischemia-reperfusion injury. The uptake of calcium into the mitochondrial matrix is regulated by the mitochondrial calcium uniporter (MCU). An endogenous enzyme, Ca2+ Calmodulin Dependent Kinase II (CaMKII) has shown to regulate cell death and have increased activity during

the expression of a gene for cardiac contractile proteins, causing increased protein synthesis, a reduction in arterial contractility and a reduction in atrial energy demands. There is an action potential prolongation of the Ca+ current at a cellular level, which prolongs the time taken for myocytes to contract and relax [ncbi.nlm.nih 1998].

Cell-surface receptors are integral membrane proteins that play a major role in signal transduction, allowing the function of Neurons, muscles and sensory organs to occur. Their basic function is to carry out the process of signal transduction by binding to an extracellular signalling molecule. Cell-surface receptors regulate gene transcription, ion flux in the neurons and growth factors. This regulation allows the human body to function with little error. They detect the smallest of changes and respond with a cascade of signalling events appropriately. I am going to describe the four main types of cell-surface receptors and the Mitogen-activated protein cascade in receptor tyrosine kinases.

Enhance the affinity of the recognition site for GABA by inducing conformational changes that make GABA binding more efficacious.

The physiological function of each receptor subtype has not been established and is currently the subject of intensive investigation (1).