Cellular Signalling
Chapter 24 pages 716-732 Outline• the endocrine system and hormones
• G-protein coupled receptors and second messengers • how do hormones contribute to metabolism
• insulin and diabetes
• we’re going to switch gears one last time and discuss how signals are sent to cells, received by cells, and processed
• but you all know by now that switching gears doesn’t mean much - in the living cell EVERYTHING IS RELATED TO EVERYTHING ELSE
• but, because of that relatedness, large multi-cellular organisms need a form of communication - if energy levels are high, α-ketoglutarate can be used for nitrogen metabolism…
- how does one cell tell another that energy levels are high
- the Cori Cycle is the shuffling of glucose metabolites to and from the liver - wouldn’t it be nice if the liver knew what to expect?
• communication between cells, organs, tissue-types is essential in organisms as large and complex as us
- so, how do we do it…?
The Endocrine System
• there are two primary means of communication in our bodies: - the nervous system: electrical impulses between cells (neurons)
- weirdos like this stuff (like the ‘other’ Dr. Mennella)
- the endocrine system: chemical signals (hormones) sent through the blood Similarities & Differences Between the Nervous and Endocrine Systems
Similarities:
• both transmit information
• both detect and respond to stimuli from inside and outside the body • both rely on chemical systems and “ligand/receptor” interactions Differences:
• signals from the NS are direct; signals from the ES are not • NS signals tend to be short-lived; ES signals can be long-lasting
But, what do we mean when we say the signals from the nervous system are direct, while the signals from the endrocrine system are not?
Nervous System Analogy:
when you mail a letter, you address it and you only send one it gets delivered to your intended recipient
your message has been sent and received only your recipient gets the one letter you sent Endocrine System Analogy:
but the endocrine system works more like a sales flyer EVERYONE gets the message
however, only those who are interested in the message pay any attention to it everyone else just ignores the message
- and endocrinology is the study of hormones and how they work
• endocrine glands in the body release hormones directly into the bloodstream
- once in the blood, these hormone flyers are delivered to every cell in the body (once a minute) - but only cells with a RECEPTOR for a particular hormone can sense that hormone’s presence
- only if you have the receptors, are you interested Hormones
• hormones can be steroids (based on the cholesterol molecule) - examples are estrogen, progesterone, testosterone
• hormones can be peptides (small proteins; still encoded in DNA) - examples are insulin, endorphin, vasopressin
• hormones can be modified derivatives of single amino acids - an example is epinephrine
• hormones are the primary contributor to HOMEOSTASIS - everything staying as it should; “steady as she goes”
• hormones also induce physiological changes as a response to environmental stimuli - see a tiger charging at you…?
- fight-or-flight
- the result of adrenaline; the hormone epinephrine • hormones also regulate and dictate development
- growth, sexual maturation
• hormones can even change the very wiring of your brain! - just ask Dr. Mennella (the imposter…)
• typically, the release of hormone is regulated by feedback
- hormone levels themselves, or their physiological effects result in the endocrine gland reducing release
• however, it’s never quite that simple…. - greater complexity allows greater control • insulin is released as a result of high blood sugar
- insulin release is stopped as a result of low blood sugar - that’s feedback
- but another hormone is constantly opposing insulin and so… • in brief, here’s how it works…
• the body has only one real system with which to perceive the world - the nervous system
• within the brain is a region called the HYPOTHALAMUS
- this structure is the interface between the nervous and endocrine systems - it speaks both languages
• the hypothalamus receives information from the brain as neuronal impulses and releases hormones as a result
- but the hypothalamus only talks to one thing… • the PITUITARY gland
- the pituitary then releases numerous different hormones that: - cause physiological changes in the body, or…
- signal other endocrine glands to release their hormones which cause physiological changes (note: feedback)
• so, the hypothalamus is the fat CHAIRMAN OF THE BOARD
• the chemical identity of hormones plays a large role in how they convey their message - the steroid hormones are largely hydrophobic
- therefore, they can easily pass directly through the cell membrane and do not require a channel
- once in the cytoplasm, they typically bind a partner protein, enter the nucleus and affect transcription
- in this way, they alter protein synthesis (and, it’s all about the proteins!)
- the non-steroid hormones can not cross the cell membrane and bind to receptors displayed on the cell surface
- this ‘ligand/receptor’ binding causes a signal to be sent into the cell
- it’s like answering the phone for someone else and taking a message to pass along ‘later’ (or in this case, indirectly)
Signal Transduction
• when a non-steroidal hormone does bind to its receptor on the cell surface it sets off a cascade of events that eventually generates whatever physiological response is necessary
• this cascade is triggered by the hormone binding the receptor, but it is carried or ‘transduced’ into the cell by a SECOND MESSENGER
• it is the second messenger that actually brings about change in the cell as a result of hormone binding receptor
• cAMP (cyclic adenosine-monophosphate) is a common second messenger
• cAMP is made as an indirect result of a hormone binding a G-PROTEIN COUPLED RECEPTOR • a hormone binds to a G-protein coupled receptor
- called that because it is coupled to a G protein
• this binding causes the enzyme ADENYLATE CYCLASE to do what its name suggests… … cyclize ATP to cAMP
• when the hormone binds the receptor, this signals the G protein to become active
- the active G protein translocates to adenylate cyclase and activates it causing cAMP to be made
• the G protein is given that name because it can bind GTP when active and GDP when inactive - the hormone-bound receptor initiated the GDP for GTP swap thereby activating the protein • this is how we turn the system on, but signals must also be turned off
- if you keep giving your friend the message that the cable guy is coming tomorrow, sooner or later that message will be wrong
• the G protein itself has GTPase activity - it can hydrolyze GTP to GDP
• which did the active G protein bind…?
• as the G protein hydrolyzes GTP to GDP, it is bound to GDP – this is the inactive form - and so, it translocates back to the receptor to repeat the process again once the cell
receives a new signal
- essentially, the G protein turns itself off after awhile
• all that stuff (the receptor, the G protein, adenylate cyclase) is literally stuck at the interior face of the cell membrane
- but, we’re trying to get a message into the cell • cAMP carries the message into the cell
- hence, it is our second messenger
• cAMP as a molecule has no informational value
- PROTEIN KINASE A
- what do you think this protein does…?
• and remember, we discussed that phosphorylation is often an ON/OFF switch (which state means what is arbitrary…)
- it is protein kinase A that will achieve the physiological response
• there are over 20 G proteins and 100s of G protein coupled receptor systems • this is a widely used system
Calcium as a Second Messenger
• calcium serves as a second messenger in another G-protein coupled receptor system - this system also uses a membrane component called PIP2
(phosphatidylinositol 4,5-bisphosphate)
• again, of course, it begins with hormone binding to its receptor on the outside of the cell - this activates the G protein: same as before (GTP for GDP swap)
- but this time the active G protein activates PHOSPHOLIPASE C • phospholipase C hydrolyzes (splits) PIP2 into two other molecules
- IP3: which also serves as a second messenger
- it leaves the membrane and travels to the cell’s interior - DAG: which remains in the membrane and activates PROTEIN KINASE C
• protein kinase C phosphorylates many target proteins including calcium channels - this allows more calcium into the cell
• IP3 goes to the ER and triggers the release of calcium from there
• calcium binds the protein CALMODULIN which becomes active
• active calmodulin activates a kinase which then phosphorylates target proteins that go do stuff
Hormones and the Control of Metabolism
• we now have a system where different parts of the body can literally communicate with each other
- and we’ve spent an enormous amount of time this semester discussing the entangled web of crosstalk in metabolism
- so, let’s bridge the two…
• three hormones play a role in carbohydrate metabolism - adrenaline, glucagon, and insulin
• adrenaline acts on muscles causing them to release their selfish stores of glucose to increase output for fight-or-flight
• glucagon acts of the liver causing it to release its selfless stores of glucose to help the body out when blood-glucose levels fall
• insulin causes glucose to be taken out of the blood when levels are high
• feedback plays a large role in this metabolism and ensures that blood glucose levels remain remarkably constant
• whenever adrenaline or glucagon binds to its receptor, it activates a large number of G proteins
- this amplifies the signal
• each active G protein repeatedly stimulates an adenylate cyclase protein until that G protein hydrolyzes its GTP
- this amplifies the signal again
• and once protein kinase A is active, it goes and phosphorylates many many target proteins before being turned off
• this describes a CASCADE
- a series of amplifying steps that allow a single hormone molecule to exert a fast and dramatic physiological effect
• a single released glucagon molecule can cause 100s to 1000s of glucose molecules to be released
• the same is true of adrenaline
- the particular pathways each of these hormones use to exert their effects are different - but the principles of amplification and the end result (glucose release) are the same
Insulin
• there’s more to insulin than meets the eye
• insulin is a peptide hormone (51 amino acids) released by the pancreas - it is made in an inactive (pro-) form and cleaved to active form
• the insulin receptor is a member of the TYROSINE RECEPTOR KINASE class - these are not G protein coupled receptors
- they work by dimerizing and directly phosphorylating target proteins themselves - this results in less amplification…
- why…?
• the phosphorylated target proteins go off and cause the physiological changes in the cell that are necessary
• insulin’s primary function is to signal muscle and adipose cells to take up glucose from the blood when blood glucose levels are too high
• when insulin binds to its receptor, this signals the cell to move glucose transporter proteins to the cell membrane
- a door for glucose to enter through is placed in the cell’s membrane to allow glucose to leave the blood
- once glucose leaves the blood, obviously blood-glucose levels fall • insulin also affects many different enzymes
- it down regulates glycogen phosphorylase and upregulates glycogen synthase (the exact opposite of glucagon)
- it stimulates glycolysis by activating phosphofructokinase
• obviously, when this system goes awry consequences can be severe
Diabetes
• in Type I (or juvenile) diabetes, the pancreas does not make enough insulin for the body - the only remedy for this is daily insulin shots
• in Type II (or adult-onset) diabetes, normal levels of insulin are produced, but it appears as though the hormone does not bind the receptor properly or the cell does not receive the signal - the causes of this type of diabetes is still under investigation
• throughout the entire course, two things have been evident (I hope)
- the body is a remarkable machine of enormous complexity and fine/precise monitoring and control
- but, with that complexity and entanglement comes a price… … there are few ‘small’ problems
- as hearty as life is, it (we) is also quite fragile…
Summary
• there are two primary means of communication in our bodies: - the nervous system and the endocrine system
• endocrine glands release hormones directly into the bloodstream - once in the blood, these hormones are delivered to every cell - but only cells with a RECEPTOR can sense them and respond • within the brain is a region called the HYPOTHALAMUS
- it is the interface between the nervous and endocrine systems
- it talks only to the PITUITARY which releases numerous hormones that cause physiological changes in the cell or signals other endocrine glands to release their hormones
• when a non-steroidal hormone does bind to its receptor on the cell surface it sets off a cascade of events
- a hormone binds to a G-protein coupled receptor; this binding causes ADENYLATE CYCLASE to cyclize ATP to cAMP
- cAMP carries the message into the cell by activating a single protein - PROTEIN KINASE A • we also discussed a different G-protein coupled receptor
• we discussed how signals are amplified in G-protein coupled systems and not in tyrosine kinase receptor systems
• three hormones play a role in carbohydrate metabolism - adrenaline, glucagon, and insulin
• and, we ended with a very brief discussion on insulin and diabetes
