1 Signal Transduction 1: G Protein Coupled Receptors
1 Signal Transduction 1: G Protein Coupled Receptors
Introduction
Signaling means communication of information. Familiar biological examples include actions of endocrine hormones and neurotransmitters.
Cellular signaling requires at least four steps.
- creation or release of a chemical as a message,
- binding of the message molecule to a receptor protein at the target,
- initiation of a response at the target, and
- removal of the message.
Often the response in the target cell is an intracellular message, sometimes called a second messenger, that is recognized by another internal receptor and initiates another response. Ultimately a cascade of such intracellular events may produce several biological outputs. Examples of intracellular second messengers are rises of cyclic AMP or of Ca2+, and examples of responses are speeding of heart rate or inducing gene expression. Over two hours class hours we will discuss three classes of receptors: the G protein coupled receptors, the tyrosine kinase receptors, and the nuclear receptors.
This chapter focuses on G protein-coupled receptors (GPCRs), which represent the largest family of plasma membrane receptors. The human genome contains over 800 GPCR genes. Among the ligands for GPCRs are monoamine neurotransmitters (adrenaline, noradrenaline, serotonin, dopamine, histamine), many peptide hormones, light photons, odorants, and sweet, bitter, and “umami” tastes (Box A). For many of these extracellular stimuli there are multiple different GPCRs, meaning that the same extracellular signal might give rise to different intracellular responses depending on which receptor subtype it encounters. For example, there are three major types of receptors for adrenaline and noradrenaline, called α1, α2, and β adrenergic receptors. In turn, each receptor type is further diversified by being encoded by three slightly different genes, making a total of nine adrenergic receptor genes altogether. The GPCR family is exceptionally important clinically, as demonstrated by the fact that 35% of FDA-approved drugs target GPCRs or elements of their down-stream signaling pathways.
Box A: Diversity of GPCR ligands
Neurotransmitters
- norepinephrine
- adenosine
- histamine
- serotonin
- dopamine
- cannabinoids
- opiates
- acetylcholine
- GABA
- glutamate
Peptide hormones
- endothelin
- glucagon
- angiotensin II
- GSH, FSH, CRH
- GnRH, ACTH
Tastants, oderants, light
Session Learning Objectives
Learning objective 1. Describe in detail the activation of GPCR signaling including receptors, ligands & heterotrimeric G-proteins
Learning objective 2. Know different G-proteins coupling to different second messengers
Learning objective 3. Describe two effector pathways: cAMP and PLC
Learning objective 4. Know how GPCR signaling is terminated
GPCR Structure and Function.
GPCRs are integral plasma membrane proteins with 7 transmembrane segments (Fig. 1). GPCRs transduce signals from extracellular ligands to signals in intracellular relay proteins, t