Friday, February 22, 2013

Types of Receptors - Part 1

Before understanding the pathways and mechanisms of complicated cell-cell signaling, lets make it easy by first understanding the different types of cell receptors and how do they function. Understanding this, will make the cell-cell signaling very clear and easy to remember.

From our previous posts, we can recall that cell-cell signaling requires binding of the signaling molecules to the cell-surface receptors on the target cells. So, lets first understand different classes of cell surface receptors with their functioning. In the next few articles, we will be learning about classes of cell surface receptor then followed by the pathways and the mechanisms of signaling and communication (downstream signaling).

Lets start our discussion with the first family of cell receptors which is also the largest - G-Protein Coupled Receptors, abbreviated as GPCRs. You might be thinking what is this "G-protein"? The G-protein stands for guanine nucleotide binding protein. The G-protein coupled receptors or GPCRs utilizes these G-proteins as an intermediate to transmit signals to intracellular targets. There are around thousands of GPCRs. Do you know, that these receptors are also responsible for our various senses like smell, sight and taste? Isn't it interesting to know how it works? Before that, lets understand the structure of GPCRs.
The G-protein coupled receptors consists of proteins which are characterized by seven α-helices (as can be seen in the adjacent figure) that span the membrane and hence are called membrane-spanning α-helices.
G proteins consists of three subunits as α, β and γ. They are also referred to as heterotrimeric G proteins. What is the role of these subunits, we will see in the functioning of the receptor. Before understanding the functioning, just remember:
α-subunit bound to GDP ---- Inactive State
α-subunit bound to GTP ---- Active State
The α-subunit binds to guanine nucleotide which regulates G-protein activity. In the resting stage, the α-subunit is bound to GDP in association with β and γ subunits (here, α-subunit bound to GDP is inactive state) (in the adjacent figure - the topmost diagram). When the hormone binds to the extracellular domain of these receptors, there is a change in the conformation of the receptors such that the cytosolic domain of the receptor interacts with the G-protein. This leads to the release of GDP from α-subunit and in turn it gets exchanged with GTP. This α-subunit which is now bound to GTP (active state), dissociates with β and γ subunits and these two subunits remain together as βγ complex (the left diagram in the above figure).
The α-bound GTP and βγ complex functions by interacting with their respective targets and gives an intracellular response. When there is hydrolysis of GTP, the activity of  α-subunit is terminated and this inactive α-subunit (which is bound to GDP) then re-associates with βγ complex and the cycle starts again.
There is a wide range of α, β and γ subunits. For example, mammalian genome codes for around 20α subunits, 5β subunits and 12γ subunits. Different G proteins associate with different receptors and hence, there are distinct intracellular targets.

(Note: What makes it binds to GTP after conformational change. GDP (guanine dinucleotide phosphate has two phosphate groups while, guanine trinucleotide phosphate, GTP has three phosphate groups. So, when there is an active state (conformational change), the conformation is such that it can accommodate 3 phosphate groups and hence GDP is replaced by GTP.